Radiation nanomedicines for cancer treatment: a scientific journey and view of the landscape

Reilly, Raymond M.; Georgiou, Constantine J.; Brown, Madeline K.; Cai, Zhongli

doi:10.1186/s41181-024-00266-y

Review
Open access
Published: 04 May 2024

Radiation nanomedicines for cancer treatment: a scientific journey and view of the landscape

Raymond M. Reilly ORCID: orcid.org/0000-0003-1038-7993^1,2,3,4,5,
Constantine J. Georgiou¹,
Madeline K. Brown¹ &
…
Zhongli Cai¹

EJNMMI Radiopharmacy and Chemistry volume 9, Article number: 37 (2024) Cite this article

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Abstract

Background

Radiation nanomedicines are nanoparticles labeled with radionuclides that emit α- or β-particles or Auger electrons for cancer treatment. We describe here our 15 years scientific journey studying locally-administered radiation nanomedicines for cancer treatment. We further present a view of the radiation nanomedicine landscape by reviewing research reported by other groups.

Main body

Gold nanoparticles were studied initially for radiosensitization of breast cancer to X-radiation therapy. These nanoparticles were labeled with ¹¹¹In to assess their biodistribution after intratumoural vs. intravenous injection. Intravenous injection was limited by high liver and spleen uptake and low tumour uptake, while intratumoural injection provided high tumour uptake but low normal tissue uptake. Further, [¹¹¹In]In-labeled gold nanoparticles modified with trastuzumab and injected iintratumourally exhibited strong tumour growth inhibition in mice with subcutaneous HER2-positive human breast cancer xenografts. In subsequent studies, strong tumour growth inhibition in mice was achieved without normal tissue toxicity in mice with human breast cancer xenografts injected intratumourally with gold nanoparticles labeled with β-particle emitting ¹⁷⁷Lu and modified with panitumumab or trastuzumab to specifically bind EGFR or HER2, respectively. A nanoparticle depot (nanodepot) was designed to incorporate and deliver radiolabeled gold nanoparticles to tumours using brachytherapy needle insertion techniques. Treatment of mice with s.c. 4T1 murine mammary carcinoma tumours with a nanodepot incorporating [⁹⁰Y]Y-labeled gold nanoparticles inserted into one tumour arrested tumour growth and caused an abscopal growth-inhibitory effect on a distant second tumour. Convection-enhanced delivery of [¹⁷⁷Lu]Lu-AuNPs to orthotopic human glioblastoma multiforme (GBM) tumours in mice arrested tumour growth without normal tissue toxicity. Other groups have explored radiation nanomedicines for cancer treatment in preclinical animal tumour xenograft models using gold nanoparticles, liposomes, block copolymer micelles, dendrimers, carbon nanotubes, cellulose nanocrystals or iron oxide nanoparticles. These nanoparticles were labeled with radionuclides emitting Auger electrons (¹¹¹In, ^99mTc, ¹²⁵I, ¹⁰³Pd, ^193mPt, ^195mPt), β-particles (¹⁷⁷Lu, ¹⁸⁶Re, ¹⁸⁸Re, ⁹⁰Y, ¹⁹⁸Au, ¹³¹I) or α-particles (²²⁵Ac, ²¹³Bi, ²¹²Pb, ²¹¹At, ²²³Ra). These studies employed intravenous or intratumoural injection or convection enhanced delivery. Local administration of these radiation nanomedicines was most effective and minimized normal tissue toxicity.

Conclusions

Radiation nanomedicines have shown great promise for treating cancer in preclinical studies. Local intratumoural administration avoids sequestration by the liver and spleen and is most effective for treating tumours, while minimizing normal tissue toxicity.

Background

Radiation nanomedicine is a term that our group first used in 2015 to describe gold nanoparticles (AuNPs) conjugated to the anti-epidermal growth factor receptor (EGFR) monoclonal antibody panitumumab (Vectibix^®, Amgen) and labeled with β-particle emitting, ¹⁷⁷Lu for local treatment of EGFR-positive breast cancer (BC) (Yook et al. 2015). The term may be applied generally to describe nanoparticles (NPs) labeled with radionuclides that emit α- or β-particles or Auger electrons (AE) that are intended for cancer treatment. These radionuclides may also emit γ-photons or positrons which enable single photon emission computed tomography (SPECT) or positron emission tomography (PET), respectively. This allows assessment of the tumour and normal tissue uptake of the radiation nanomedicines by imaging, which aids in estimating the radiation absorbed doses in tumours and normal organs. However, this article does not focus on the use of radiolabeled NPs for tumour imaging, but instead on their therapeutic applications. Radiation nanomedicines may be constructed from a wide range of NPs including liposomes and polymeric micelles, graphene or carbon-based nanostructures, dendrimers and inorganic NPs, e.g. gold nanoparticles (AuNPs) (Fig. 1). They may be administered systemically [e.g. intravenous (i.v.) injection] or delivered locally [e.g. intratumoural (i.t.) injection]. Systemic administration relies on passive or active targeting to selectively deliver NPs to tumours. Passive targeting is mediated by the Enhanced Permeability and Retention (EPR) effect which is explained by increased permeability of tumour blood vessels but poor lymphatic drainage resulting in tumour accumulation of NPs (Shinde et al. 2022). Active targeting requires conjugation of biomolecules (e.g. monoclonal antibodies or peptides) to NPs to specifically bind tumour-associated receptors or other cell-surface proteins (Goddard et al. 2020). We describe here our 15 years scientific journey studying radiation nanomedicines for treatment of tumours and their preclinical evaluation. At the same time, we present a contextual view of the broader landscape of radiation nanomedicines reported by other research groups. We hope that our perspective, combined with a discussion of the landscape, will enable readers to appreciate the great promise and challenges of radiation nanomedicines for cancer treatment.

Main text

Scientific journey: the beginning

Our scientific journey began with studies of trastuzumab-conjugated AuNPs for X-ray therapy (XRT) radiosensitization of human epidermal growth factor receptor-2 (HER2)-positive BC (Chattopadhyay et al. 2010). We hypothesized that conjugation of trastuzumab (Herceptin, Roche) to AuNPs would target AuNPs to HER2 positive BC cells and internalize them into these cells by HER2-mediated internalization. In theory, this would maximize their radiosensitization effects in vitro combined with XRT, especially since more radiobiologically-damaging AE generated by photoelectric interaction of X-rays with AuNPs have a subcellular range. Monte Carlo (MC) simulations have shown that internalization into the cytoplasm and particularly nuclear uptake of AuNPs in cancer cells are important factors to maximize their radiosensitization properties (Cai et al. 2013; Lechtman et al. 2011). We further hypothesized that trastuzumab-conjugated AuNPs would be actively targeted to HER2-positive human BC xenografts in vivo in mice after i.v. injection, allowing studies of AuNP radiosensitization combined with XRT. In the next section, we provide a view of the landscape of the application of AuNPs as radiosensitizers combined with XRT for treatment of cancer.

Landscape: gold nanoparticles as radiosensitizers of XRT

Gold is a high atomic number (Z = 79) and dense (19.3 g/cm³) element that enhances the radiobiological effectiveness (RBE) of XRT, since X-rays are absorbed more efficiently by gold than soft tissues due to Compton and photoelectric interactions (Chen et al. 2020) (Fig. 2a). Interactions of X-rays with inner shell electrons in the gold atom results in the production of photoelectrons (PE) which create a vacancy in the shell, that is then filled by the decay of an electron from a higher shell, creating a subsequent vacancy with a X-ray photon emission or two subsequent vacancies with the emission of an electron called an AE. These vacancies are filled by the decay of higher shell electrons, and so on, in what is termed an Auger cascade. Ultimately, the Auger cascade results in the ejection of a series of outer shell AE, or emission of low energy X-rays. Both PE and AE are high linear energy transfer (LET) forms of radiation that are more radiobiologically damaging than low LET X-rays. PE have higher energy than AE and a longer range in tissue (e.g. ~ 100 μm for a 100 keV PE), while AE have much lower energy and penetrate much shorter distances (e.g. < 10 nm) (Hainfeld et al. 2008). The most widely studied form of gold for radiosensitization are AuNPs, which are typically spherical gold particles with a diameter < 100 nm (Chen et al. 2020). In addition to generating high LET, several biological mechanisms have been proposed to explain AuNP radiosensitization by PE and AE including: (i) increased production of reactive oxygen species (ROS), (ii) disruption of the cell cycle, resulting in accumulation of cells in the more radiosensitive G2/M-phase, (iii) interference in DNA repair, and (iv) a bystander effect that extends the effects of X-radiation to non-irradiated cells (Her et al. 2017; Rosa et al. 2017).

Great interest in AuNP radiosensitization was sparked by a landmark report in 2004 by Hainfeld et al. (2004) who studied XRT of subcutaneous (s.c.) EMT-6 murine mammary carcinoma tumours in Balb/c mice using 250 kVp X-rays with or without intravenous (i.v.) injection of AuNPs (1.9 nm). Tumour growth arrest and shrinkage was achieved in mice treated with XRT combined with AuNPs, but tumour growth was only slowed in mice that received XRT alone, and tumours grew rapidly in mice treated with AuNPs without XRT and in untreated mice (Fig. 2b). Moreover, AuNP radiosensitization prolonged the survival of XRT treated mice, dependent on the amount of AuNPs administered (Fig. 2c). Despite these encouraging results, a limitation was the high amount of gold administered to mice (1.35 g/kg or 2.7 g/kg) that was required to achieve sufficient concentrations for radiosensitization (0.5–1% of tumour weight equivalent to 10 mg of gold per g of tumour) (Hainfeld et al. 2008; Roeske et al. 2007). These amounts in some cases were just slightly lower than the lethal dose-50% (LD₅₀ ~ 3.2 g/kg). Nonetheless, this study demonstrated proof-of-principle and led to many investigations of AuNPs as radiosensitizers, including Monte Carlo (MC) dose simulations, studies of their radiosensitizing effects in vitro by decreasing the clonogenic survival (CS) of cancer cells exposed to XRT, and in vivo studies of tumour growth inhibition combined with XRT (Dheyab et al. 2023; Hainfeld et al. 2008; Her et al. 2017). The radiosensitization properties of AuNPs are defined by a dose-enhancement factor (DEF) which is the radiobiological effect (e.g. decreased CS) for XRT combined with AuNPs vs. XRT alone. DEFs for cancer cells exposed in vitro to XRT combined with AuNPs vs. XRT alone have ranged from 1.1 to 1.9, but most were 1.1–1.4 (Her et al. 2017). There have been fewer studies of AuNP radiosensitization in vivo, but in addition to the study by Hainfeld et al. (2004), AuNP radiosensitization has been reported in several other mouse tumour models (Her et al. 2017).

MC modeling revealed that several factors control the dose enhancement by AuNPs including X-ray energy, concentration and location of AuNPs in cells and the size of AuNPs. The strongest absorption of X-ray energy occurs at the K-edge (80.7 keV), L-edges (11.9–14.4 keV) or M-edges (2.2–3.4 keV) of gold (Hainfeld et al. 2008). These edges represent the minimum energy of an incident X-ray needed to eject an electron from a particular shell. However, radiation treatment of cancer is most often delivered by much higher energy (megavoltage) photons that are not optimally absorbed by gold. Lechtman et al. (2011) predicted that 300-times greater gold concentration in tumours (1560–1760 mg/g) would be required to achieve a twofold increase in the absorbed dose (i.e. DEF = 2) for 6 MV photons than for an ¹²⁵I brachytherapy source with lower average energy = 27 keV (5.3–6.3 mg/g). These gold concentrations are very high, and likely not feasible for radiosensitization with high energy photons. The size of AuNPs affects radiosensitization because a proportion of low energy AE produced by photoelectric interaction with X-rays are absorbed by the NPs themselves, and this increases for larger AuNPs. In addition, the AEs emitted have a range < 1 μm, and thus nuclear localization of AuNPs may be needed to maximize DNA damage (Lechtman et al. 2011). Dosimetry modeling reveals that nuclear uptake maximizes the DEF (Lechtman et al. 2013). Cai et al. (2013) defined a new term: Nuclear Dose Enhancement Factor (NDEF) which predicts the radiosensitization effects of AuNPs. By MC simulation the effect of various factors on NDEF were studied. These included different photon sources [monoenergetic X-rays (10–100 keV), X-ray beam (100 kVp) or ¹²⁵I or ¹⁰³Pd brachytherapy seeds], different numbers or diameter (5, 30 or 50 nm) of AuNPs located on the cell surface, in the cytoplasm or nucleus of human BC cells or in the extracellular space as well as different cell geometries (single cell, monolayer or cell cluster). NDEFs were greatest for AuNPs in the nucleus, and using X-rays with energy of 15 or 40 keV. The NDEF estimated by monolayer cell geometry was most correlated with the experimentally measured AuNP radiosensitization in CS assays. The cellular concentration of gold needed to achieve an NDEF = 2 for X-rays combined with AuNPs versus X-rays alone for 30 nm AuNPs was 5.1 mg/g, when AuNPs were placed in the nucleus compared to 10 mg/g in the cytoplasm or the cell surface. These model-predicted concentrations agree with those used by Hainfeld et al. in mice with EMT-6 tumours for XRT radiosensitization (Hainfeld et al. 2004) (10 mg gold/g).

Journey: HER2-targeted AuNPs for XRT radiosensitization

To explore AuNP radiosensitization of XRT of HER2-positive BC, we conjugated AuNPs (30 nm) to trastuzumab through a 5 kDa cross-linker: orthopyridyldisulphide polyethylene glycol-N-hydroxysuccinimide valerate (OPSS-PEG_5K-SVA). Trastuzumab-PEG-OPSS were linked to AuNPs by a gold-thiol bond formed by reaction with the OPSS group (Chattopadhyay et al. 2010). Trastuzumab was modified with ~ 7 OPSS-PEG_5K chains per molecule and each AuNP was conjugated to ~ 14 trastuzumab-PEG_5K-OPSS. AuNPs were then surface-coated with 2 kDa PEG_2K-SH chains to prevent aggregation. These modifications increased the hydrodynamic diameter of the AuNPs to ~ 60 nm. Darkfield microscopy showed HER2-specific binding, internalization and perinuclear localization of trastuzumab-AuNPs by SK-BR-3 human BC cells. Exposure of SK-BR-3 cells to 300 kVp X-rays combined with HER2-targeted AuNPs increased DNA DSBs by 5.5-fold, while non-targeted AuNPs increased DNA DSBs by 3.3-fold compared to XRT alone. DNA damage was determined by immunofluorescence microscopy for γ-H2AX, a phosphorylated form of histone-2A that accumulates at sites of unrepaired DNA DSBs (Mah et al. 2011). Subsequently, we investigated HER2-targeted AuNPs combined with 100 kVp X-rays for decreasing the CS of MDA-MB-361 human BC cells in vitro and for inhibiting the growth of s.c. MDA-MB-361 tumour xenografts in vivo in athymic mice (Chattopadhyay et al. 2013). The dose required to decrease the CS of MDA-MB-361 cells to 0.10 (D₁₀) was 7.6 Gy for X-rays, but was 5.9 Gy and 4.8 Gy for XRT combined with non-targeted or HER2-targeted AuNPs, respectively. These D₁₀ values corresponded to a DEF = 1.3 or 1.6 for non-targeted or HER2-targeted AuNPs, respectively. HER2-targeted AuNPs inflicted more DNA DSBs than non-targeted AuNPs combined with XRT. To study the radiosensitizing effects of AuNPs in vivo, we employed i.t. injection of HER2-targeted AuNPs in mice with s.c. MDA-MB-361 tumours to achieve a sufficient concentration of gold for radiosensitization (5–10 mg/g) (Cai et al. 2013). The selection of i.t. injection was informed by an earlier imaging and biodistribution study that showed that i.v. injected HER2-targeted AuNPs labeled with ¹¹¹In exhibited very low tumour uptake at 48 h post-injection (p.i.) [1.2 percent injected dose/g (%ID/g)] and high uptake in the spleen (19.2% ID/g), liver (2.7% ID/g) and kidneys (2.3% ID/g) (Chattopadhyay et al. 2012) (Fig. 3). In contrast, i.t. injection of ¹¹¹In-labeled HER2-targeted AuNPs resulted in 25-fold greater tumour uptake (29.6% ID/g) and decreased spleen uptake by 11-fold (1.8% ID/g) while moderately reducing uptake in the liver (1.6% ID/g) and kidneys (1.5% ID/g). Most NPs injected i.v. are recognized and captured by the mononuclear phagocyte system (MPS) which includes the lymph nodes, spleen and liver. Despite shielding of NPs by PEG, spleen and liver uptake remain a major obstacle to their delivery to tumours (Mills et al. 2022). Intratumoural injection of HER2-targeted AuNPs minimized spleen and liver uptake and achieved a tumour concentration of gold (4.8 mg/g) that was expected to be sufficient to radiosensitize tumours to XRT (Cai et al. 2013). Moreover, this tumour concentration of gold was achieved by i.t. injection of only 0.8 mg of AuNPs (0.04 g/kg) which was 33-fold lower than that injected i.v. in mice with EMT-6 tumours for XRT radiosensitization (2.7 g/kg) by Hainfeld et al. (2004), improving the safety profile of AuNP radiosensitization. Treatment of mice with s.c. MDA-MB-361 tumours with HER2-targeted AuNPs combined with 11 Gy of XRT decreased tumour volume by ~ twofold over 5 weeks, while tumours treated with only XRT increased in size. No normal tissue toxicity was found in mice treated with XRT alone or combined with HER2-targeted AuNPs, assessed by monitoring body weight and hematology and blood biochemistry analyses.

Journey: radiation nanomedicine for HER2-positive BC

Trastuzumab-AuNPs labeled with ¹¹¹In were used in the previously described XRT radiosensitization study to compare their tumour and normal tissue uptake after i.v. or i.t. injection in mice with s.c. MDA-MB-361 human BC xenografts by SPECT and by ex vivo γ-counting of tissues (Chattopadhyay et al. 2012). ¹¹¹In (t_1/2 = 2.8 d) decays by electron capture (EC) emitting two γ-photons [Eγ = 171 keV (90%) and Eγ = 245 keV (94%)] that allow SPECT and 7.4 AEs (average energy = 0.9 keV) and 0.2 internal conversion electrons (CEs) per decay (average energy = 27.9 keV) that may be used for radiotherapeutic purposes (Ku et al. 2019). [¹¹¹In]In-BnDTPA-trastuzumab-AuNPs (Fig. 4a) were synthesized by conjugation of AuNPs to [¹¹¹In]In-Bn-DTPA-PEG_2K-SH (Chattopadhyay et al. 2012). [¹¹¹In]In-Bn-DTPA-PEG_2K-SH was synthesized by reaction of PEG_2K-NH₂ with S-2-(4-Isothiocyanatobenzyl)-diethylenetriamine pentaacetic acid (p-SCN-Bn-DTPA) then labeled with ¹¹¹In in sodium acetate buffer, pH 6.0. Based on our observation that i.t. injected [¹¹¹In]In-Bn-DTPA-PEG_2K-trastuzumab-AuNPs were strongly retained in s.c. MDA-MB-361 tumours in athymic mice and exhibited low uptake in normal tissues, we hypothesized that the AE and CE emissions of ¹¹¹In may be effective for inhibiting tumour growth at amounts that would not cause toxicity to normal tissues. This was the first time in our journey that we considered the idea of a radiation nanomedicine administered locally for treatment of tumours. We tested this idea by first determining the effectiveness of [¹¹¹In]In-Bn-DTPA-PEG_2K-trastuzumab-AuNPs for decreasing the CS of HER2-positive SK-BR-3 and MDA-MB-361 human BC cells in vitro, and for inhibiting the growth of s.c. MDA-MB-361 tumours in vivo in mice (Cai et al. 2016). [¹¹¹In]In-Bn-DTPA-PEG_2K-trastuzumab-AuNPs were specifically bound and internalized by SK-BR-3 and MDA-MB-361 cells in vitro and were transported to a perinuclear location. Nuclear localization of these AuNPs may be mediated by a nuclear translocation sequence (NLS) present in HER2 (Chen et al. 2005). The emission of AEs and CEs by ¹¹¹In in close proximity to the nucleus caused DNA DSBs (Fig. 4b) that decreased the CS of both SK-BR-3 and MDA-MB-361 cells. Most importantly, i.t. injection of 10 MBq of [¹¹¹In]In-Bn-DTPA-PEG_2K-trastuzumab-AuNPs (2.6 × 10¹² AuNPs) in mice with s.c. MDA-MB-361 human BC xenografts arrested tumour growth with no decrease in body weight which indicated no general toxicity (Fig. 4c). The absorbed dose in these tumours was high (60.5 Gy), while normal organ doses were low (< 0.9 Gy) and the whole body dose was 0.66 Gy (Fig. 4d). In mice treated with [¹¹¹In]In-Bn-DTPA-PEG_2K-trastuzumab-AuNPs, there were no significant changes in complete blood cell counts (CBC) and serum biochemistry [e.g. alanine aminotransferase (ALT) or creatinine (Cr)] compared to normal saline-treated mice, indicating no normal tissue toxicity. These results greatly encouraged us to continue investigations of a radiation nanomedicine strategy for local treatment of BC and other tumours. In the next section, we discuss the landscape of various forms of NPs labeled with AE-emitting radionuclides that have been studied for cancer treatment.

Landscape: NPs labeled with AE-emitting radionuclides

Indium-111

Song et al. (2016) conjugated 14 nm AuNPs to [¹¹¹In]In-DTPA-human epidermal growth factor (¹¹¹In]In-DTPA-EGF) by a gold-thiol bond formed with the disulfides in EGF. Up to 78 DTPA-hEGF were linked to one AuNP. [¹¹¹In]In-DTPA-EGF-AuNPs were specifically bound and internalized by EGFR-overexpressing MDA-MB-468 human BC cells and confocal fluorescence microscopy with AuNPs linked to Cy3-EGF showed perinuclear localization. Nuclear localization may be mediated by a NLS present in the EGFR that binds to importins responsible for nuclear importation of proteins (Hsu and Hung 2007). Emission of AEs by [¹¹¹In]In-DTPA-EGF-AuNPs decreased the CS in vitro of MDA-MB-468 cells, but did not decrease the CS of MCF-7 human BC cells that have low EGFR expression. Subsequently, these [¹¹¹In]In-DTPA-EGF-AuNPs were surface-coated with PEG-SH and compared to non-PEGylated forms (Song et al. 2017). PEGylation increased the hydrodynamic diameter of [¹¹¹In]In-DTPA-EGF-AuNPs from 18 to 32 nm and decreased surface charge (zeta potential) from − 24 to − 9.6 mV. PEGylated [¹¹¹In]In-DTPA-EGF-AuNPs were internalized by MDA-MB-468 and MDA-MB-231/H2N human BC cells and Cy3-EGF-AuNPs showed perinuclear localization. Unfortunately, there was high liver and kidney uptake and low tumour accumulation (0.2% ID/g) in mice with s.c. MDA-MB-468 or MDA-MB-231/H2N tumours at 72 h post-i.v. injection of non-PEGylated [¹¹¹In]In-DTPA-EGF-AuNPs. PEGylation reduced liver uptake by twofold and increased tumour uptake by 14-fold (2.8% ID/g). Co-administration of excess EGF to block EGFR on normal tissues further decreased uptake in liver, kidneys and spleen but decreased tumour uptake (1.4% ID/g). An interesting method of labeling AuNPs with ¹¹¹In by incorporating [¹¹¹In]InCl₃ into the synthesis of AuNPs was reported by Ng et al. (2014). These [¹¹¹In]In-AuNPs were further modified with arginine-glycine-aspartic acid (RGD) peptides to target α_vβ₃ integrins displayed on M21 melanoma or U87-MG glioblastoma multiforme (GBM) cells. Unfortunately, tumour uptake of [¹¹¹In]In-RGD-AuNPs at 4 h post i.v. injection in mice with s.c. M21 or U87-MG xenografts was low (0.5–1% ID/g) while liver and spleen uptake were high (18–30% ID/g and 8–12% ID/g, respectively).

Block copolymer micelles (BCMs) are NPs composed of amphiphilic copolymers that form micellar structures containing a hydrophobic core in which drugs may be loaded, surrounded by a hydrophilic corona that may be modified with targeting ligands (Fonge et al. 2012). Fonge et al. (2010) constructed EGFR-targeted BCMs (13–15 nm) from MePEG₂₅₀₀-b-PCL₁₂₀₀ and [¹¹¹In]In-DTPA-PEG₃₀₀₀-b-PCL₁₆₀₀ copolymers and evaluated their uptake in MDA-MB-468, MDA-MB-231 and MCF-7 human BC cells with high, moderate or low EGFR density, respectively. The effect of exposure of MDA-MB-468 or MCF7 cells in vitro to EGFR-targeted [¹¹¹In]In-DTPA-PEG-EGF BCMs or non-targeted [¹¹¹In]In-DTPA-PEG BCMs was assessed in CS assays. Uptake in MDA-MB-468, MDA-MB-231 or MCF-7 cells was dependent on the EGFR expression level, but most activity remained on the cell surface, with a small amount of internalization into the cytoplasm and nucleus. Nonetheless, [¹¹¹In]In-DTPA-PEG-EGF BCMs strongly decreased the CS of MDA-MB-468 cells that have high EGFR expression, but not MCF-7 cells with low EGFR expression. Non-targeted [¹¹¹In]In-DTPA-PEG BCMs were not cytotoxic. Interestingly, a comparison with [¹¹¹In]In-DTPA-EGF revealed more efficient binding of [¹¹¹In]In-DTPA-EGF than [¹¹¹In]In-DTPA-PEG-EGF BCMs to MDA-MB-468 cells and higher nuclear importation, resulting in greater cytotoxicity. [¹¹¹In]In-DTPA-EGF is a radiopeptide that has been previously reported as an AE-emitting radiotherapeutic agent for EGFR-positive BC (Reilly et al. 2000). Hoang et al. (2012) constructed HER2-targeted BCMs composed of MePEG-b-PCL, [¹¹¹In]In-DTPA-PEG-b-PCL and NLS₂-trastuzumab-Fab-PEG-b-PCL copolymers. The size of these BCMs was 35 nm and their zeta potential was + 2.0 mV. NLS₂-trastuzumab-Fab-PEG-b-PCL consisted of trastuzumab Fab linked to NLS peptides (CGYGPKKKKRKVGG) conjugated to PEG-b-PCL. These BCMs incorporated methotrexate (MTX) into the core, which was intended as a radiosensitizer for AEs emitted by ¹¹¹In, since MTX inhibits DNA repair (Costantini et al. 2010). These BCMs were specifically bound and internalized by HER2-positive SK-BR-3 and MDA-MB-361 human BC cells in vitro and the NLS₂-trastuzumab-Fab-PEG-b-PCL copolymer mediated nuclear localization. The CS of SK-BR-3 and MDA-MB-361 cells were greatly decreased by the emission of AEs by ¹¹¹In, and this was amplified by incorporating MTX into these BCMs. These HER2-targeted BCMs were not studied in vivo, but the tumour and normal tissue uptake of non-targeted BCMs composed of MePEG-b-PCL and [¹¹¹In]In-DTPA-PEG-b-PCL copolymers has been studied after i.v. injection in mice with s.c. MDA-MB-231 tumour xenografts (Hoang et al. 2009). Similar to other NPs administered by i.v. injection, there was high liver (13% ID/g) and spleen (22% ID/g) sequestration but tumour uptake was relatively high (9% ID/g). Therapeutic effectiveness and toxicity in vivo were not assessed.

Other forms of NPs labeled with ¹¹¹In have been studied as radiation nanomedicines. Chan et al. (2013) reported that G4 polyamidoamine (PAMAM) dendrimers conjugated to trastuzumab and multiple DTPA for high specific activity (SA) labeling with ¹¹¹In were internalized into the cytoplasm and nucleus of HER2-positive SK-BR-3 cells. Emission of AEs caused DNA DSBs which decreased the CS of these cells. Thomas et al. (2019) conjugated [¹¹¹In]In-DTPA-EGF to liposomes (140 nm; zeta potential = − 30 mV) that also incorporated doxorubicin for combined chemoradiotherapy of EGFR-overexpressing BC. [¹¹¹In]In-DTPA-EGF-Dox-liposomes were bound and internalized by EGFR-overexpressing MDA-MB-468 human BC cells and localized in the nucleus. Emission of AEs by ¹¹¹In caused DNA DSBs which were amplified by the DNA damaging properties of doxorubicin, and strongly decreased the CS of MDA-MB-468 cells. One interesting aspect of this study was that focused ultrasound was applied to s.c. MDA-MB-468 tumours to improve the tumour penetration in vivo of [¹¹¹In]In-DTPA-EGF-Dox-liposomes following i.v. injection in mice. Nonetheless, tumour uptake remained very low (0.3% ID/g) at 48 h p.i. and liver and kidney uptake were high (33% ID/g and 11% ID/g, respectively), again demonstrating the challenges associated with i.v. administration of NPs.

Technetium-99 m

Jimenez-Mancilla et al. (2013) conjugated AuNPs (5 nm) to Tat (transactivation of transcription) peptides linked through a GCGC peptide spacer to bombesin peptides to target gastrin-releasing peptide (GRP) receptors on prostate cancer cells. These AuNPs were dual-labeled with the AE-emitter, ^99mTc and β-particle-emitter, ¹⁷⁷Lu by binding of [^99mTc]Tc-hydrazinonicotinyl-Tyr³-octreotide ([^99mTc]Tc-HYNIC-TOC) and [¹⁷⁷Lu]Lu-DOTA-GGC peptides to the AuNPs. Tat peptides promote cell penetration and harbour a NLS that enables nuclear importation (Costantini et al. 2008), where the AEs emitted by ^99mTc are most damaging to DNA. These radiation nanomedicines were cytotoxic against PC-3 human prostate cancer cells in vitro, reducing their proliferation by > 95%. Interestingly, although the absorbed dose in PC-3 cells from ^99mTc was 14-fold lower than ¹⁷⁷Lu (4 Gy/Bq vs. 55 Gy/Bq), dual-labeled AuNPs were eight-fold more cytotoxic than ¹⁷⁷Lu-labeled AuNPs alone, which was attributed to the greater radiobiological effectiveness of the AEs vs. β-particles. Intratumoural (i.t.) injection of dual-labeled AuNPs in mice with s.c. PC-3 tumours resulted in high tumour uptake (58% ID/g) that was retained up to 24 h p.i. (Jimenez-Mancilla et al. 2012). The absorbed dose in the tumours was 7.9 Gy/MBq but the estimated dose in the nucleus of tumour cells was 0.53 Gy/MBq, demonstrating the potential of dual labeled radiation nanomedicines for treating tumours exploiting both AEs and β-particles.

Iodine-125, Palladium-103 and Platinum-193m/195m

Zhang et al. (2019) synthesized spherical AuNPs or gold nanorods (AuNRs) conjugated to RGD peptides to target α_vβ₃ integrins and loaded with cisplatin (cis-Pt) for combined chemoradiation therapy targeting the tumour vasculature. Non-radiolabeled RGD-[¹²⁷I]I-cis-Pt-AuNRs exhibited slightly higher uptake than RGD-[¹²⁷I]I-cis-Pt-AuNPs in H1299 human non-small cell lung cancer cells in vitro, which yielded greater radiosensitization when these cells were exposed to XRT (4 Gy). RGD-[¹²⁵I]I-cis-Pt-AuNPs and RGD-[¹²⁵I]I-cis-Pt-AuNRs were accumulated in s.c. HI299 tumors in vivo in mice demonstrated by SPECT/CT, but higher uptake was found for [¹²⁵I]I-cis-Pt-AuNRs. There was high uptake in the liver and spleen. Non-radiolabeled RGD-[¹²⁷I]I-cis-Pt-AuNPs and RGD-[¹²⁷I]I-cis-Pt-AuNRs were studied for chemoradiation therapy in mice with H1299 tumors treated with XRT (6 Gy). RGD-[¹²⁷I]I-cis-Pt-AuNRs were most effective combined with XRT for inhibiting tumor growth. Chemoradiation therapy with RGD-[¹²⁷I]I-cis-Pt-AuNPs or RGD-[¹²⁷I]I-cis-Pt-AuNRs was more effective than XRT alone. This study did not examine the cytotoxic effects of the AE emissions from ¹²⁵I-labeled radiation nanomedicines, but this may be interesting to study in the future, since ¹²⁵I emits a high number of AE/decay (23.0) and total AE energy/decay (12 keV) (Ku et al. 2019). ^193mPt and ^195mPt are also attractive AE-emitting radionuclides, which emit 27.4 AE/decay and 36.6 AE/decay, respectively (total energy = 10.9 keV and 23.1 keV, respectively) (Ku et al. 2019). Wawrowicz et al. (2021) synthesized AuNPs (~ 37 nm) incorporating a platinum shell that were then PEGylated and modified with trastuzumab to target HER2-positive BC cells. Trastuzumab-PEG-[¹⁹⁵Pt]Pt-AuNPs incorporating stable ¹⁹⁵Pt were bound, internalized and transported to a perinuclear location in HER2-positive SK-OV-3 cells in vitro. The internalization and nuclear transport of trastuzumab-PEG-[¹⁹⁵Pt]Pt-AuNPs suggests that these agents incorporating the AE-emitters ¹⁹³Pt or ^195mPt may be cytotoxic to HER2-positive BC cells and provide useful radiation nanomedicines for treating BC overexpressing HER2, but further studies are needed to explore this approach.

Journey: ¹⁷⁷Lu-labeled radiation nanomedicines

A limitation of AEs is their subcellular range, which is only a few nm to < 1 μm (Ku et al. 2019). This requires binding and internalization into cancer cells, and ideally routing to the nucleus to maximize lethal DNA DSBs (Ku et al. 2019). Thus, in the next step on our journey, we explored AuNPs labeled with ¹⁷⁷Lu (t_1/2 = 6.7 d) which emits longer range (maximum 2 mm) β-particles, that are able to irradiate and kill tumour cells even without binding to, internalizing in tumour cells or translocating to the cell nucleus. ¹⁷⁷Lu emits moderate energy β-particles [Eβ_max = 0.50 MeV (78.6%), 0.38 MeV (9.1%), 0.18 MeV (12.2%)] and a γ-photon (Eγ = 208 keV (11%)] that allows SPECT imaging. EGFR-targeted radiation nanomedicines were constructed by conjugating OPSS-PEG_5K-DOTA-¹⁷⁷Lu and OPSS-PEG_5K-panitumumab to AuNPs (30 nm). Non-targeted AuNPs were synthesized by conjugating only OPSS-PEG_5K-DOTA-¹⁷⁷Lu to AuNPs (Yook et al. 2015). DOTA [2,2′,2′′,2′′′-(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid] is commonly used to chelate ¹⁷⁷Lu and other radiometals (e.g. ⁹⁰Y, ²²⁵Ac, ¹¹¹In, or ⁶⁴Cu) (Sneddon and Cornelissen 2021). Darkfield microscopy revealed binding of EGFR-targeted but not non-targeted AuNPs to EGFR-positive MDA-MB-468 human BC cells. Confocal immunofluorescence microscopy probing for panitumumab with AlexaFluor-488 anti-human IgG showed internalization of EGFR-targeted-AuNPs into these cells. Binding and internalization of [¹⁷⁷Lu]Lu-DOTA-PEG_5K-panitumumab-AuNPs were EGFR-dependent determined by subcellular fractionation studies of MDA-MB-468, MDA-MB-231 and MCF-7 cells with high, intermediate or low EGFR expression, respectively. Absorbed doses in the nucleus of MDA-MB-468 cells treated in vitro with 4.5 MBq (6 × 10¹¹ AuNPs) of EGFR-targeted [¹⁷⁷Lu]Lu-DOTA-PEG_5K-panitumumab-AuNPs (73.2 Gy) were 13-fold greater than non-targeted [¹⁷⁷Lu]Lu-DOTA-PEG_5K-AuNPs (5.6 Gy). Exposure of MDA-MB-468 cells in vitro to [¹⁷⁷Lu]Lu-DOTA-PEG_5K-panitumumab-AuNPs reduced their CS to < 0.1%. Non-targeted [¹⁷⁷Lu]Lu-DOTA-PEG-AuNPs were also cytotoxic in vitro, due to the cross-fire effect from the 2 mm range β-particles, but these were > 100-fold less cytotoxic (CS = 8.4%) than EGFR-targeted [¹⁷⁷Lu]Lu-DOTA-PEG_5K-panitumumab-AuNPs.

We subsequently compared [¹⁷⁷Lu]Lu-DOTA-PEG_5K-panitumumab-AuNPs and [¹⁷⁷Lu]Lu-DOTA-PEG_5K-AuNPs injected i.t. for treatment of s.c. MDA-MB-468 tumours in mice (Yook et al. 2016a). Imaging (Fig. 5a) and biodistribution studies (Fig. 5b) at 48 h p.i. revealed high uptake and retention in the tumour, which was twofold greater for EGFR-targeted AuNPs (197% ID/g) than non-targeted AuNPs (99% ID/g). Normal tissue uptake was very low (< 0.5% ID/g) for EGFR-targeted and non-targeted AuNPs, except for the liver (8.5–11% ID/g) and spleen (5.4–6.9% ID/g). Both [¹⁷⁷Lu]Lu-DOTA-PEG_4K(panitumumab-PEG_5K)-AuNPs and [¹⁷⁷Lu]Lu-DOTA-PEG_4K-AuNPs injected i.t. (4.5 MBq; 6 × 10¹¹ AuNPs) arrested the growth of MDA-MB-468 tumours without decreasing body weight (Fig. 5c) and significantly prolonged the survival of tumour-bearing mice. No normal tissue toxicity was found, assessed by hematology and serum biochemistry. Absorbed doses in the tumour were high for both EGFR-targeted (30.4 Gy) and non-targeted AuNPs (21.9 Gy) but normal organ doses were very low (0.04–0.6 Gy) (Fig. 5d). In contrast to our previous in vitro study which showed an advantage of EGFR-targeting for increasing the absorbed dose and cytotoxicity of ¹⁷⁷Lu-labeled radiation nanomedicines on MDA-MB-468 cells (Yook et al. 2015), in vivo in mice with s.c. MDA-MB-468 tumours, EGFR-targeting was not required. Instead, the most important observation was that after i.t. injection, AuNPs anchored ¹⁷⁷Lu in the tumour, limiting redistribution to normal tissues, resulting in high absorbed doses in the tumour but very low doses in normal organs. This achieved tumour growth arrest but no observable normal tissue toxicity. In a subsequent study, we constructed HER2-targeted radiation nanomedicines by conjugating OPSS-PEG_5K-trastuzumab and and OPSS-PEG_3K-DOTA-[¹⁷⁷Lu]Lu to AuNPs (30 nm) (Cai et al. 2017). These were specifically bound and internalized by HER2-positive BC cells in vitro and caused DNA DSBs that decreased the CS of these cells. Tumour growth in vivo was inhibited twofold after i.t. injection of 3 MBq (5.5 × 10¹¹ AuNPs) of [¹⁷⁷Lu]Lu-DOTA-PEG_3K(trastuzumab-PEG_5K)-AuNPs, but no normal tissue toxicity was found. In contrast to our earlier study that showed equivalent tumour growth inhibition for EGFR-targeted and non-targeted ¹⁷⁷Lu-labeled AnNPs (Yook et al. 2016a), in this study, non-targeted [¹⁷⁷Lu]Lu-DOTA-PEG_3K-AuNPs were not as effective as [¹⁷⁷Lu]Lu-DOTA-PEG_5K-trastuzumab-AuNPs for inhibiting tumour growth and resulted in decreased hematocrit, red blood cell and platelet counts. Two factors might be contributing to the difference of the observation on therapeutic effects between targeted vs non-targeted: (1) the injected dose (3 MBq) in the HER2 targeted study was 50% lower than in the EGFR targeted study (4.5 MBq); (2) the tumour model (MDA-MB-361 xenografts in NOD/SCID mice, tumour doubling time of 5 d for untreated control) used in the HER2 targeted study was 3.5 times more aggressive than MDA-MB-468 xenografts in CD-1 athymic mice (tumour doubling time of 17 d for untreated control) used in the EGFR targeted study. It is worth noting that CD-1 athymic mice (which lack a thymus and T-cells) have more residual immune function than NOD/SCID mice (lack of functional T cells, B cells and natural killer cells). The residual immune function could enhance the therapeutic effect of ¹⁷⁷Lu.

In these studies, we employed OPSS-PEG_5K polymers to attach [¹⁷⁷Lu]Lu-DOTA and the monoclonal antibodies, panitumumab or trastuzumab to the surface of AuNPs, but the OPSS group forms a single gold-thiol bond with AuNPs that may not be stable in vivo, particularly in the presence of competing thiol-containing biomolecules [e.g. cysteine (Cys) or glutathione (GSH)]. Thus, we next compared the stability of AuNPs conjugated to three different metal-chelating polymers (MCPs) complexed to ¹⁷⁷Lu: [¹⁷⁷Lu]Lu-DOTA-PEG_4K-OPSS, [¹⁷⁷Lu]Lu-DOTA-PEG_4K-lipoic acid (LA) and PEG_2K-pGlu(DOTA-[¹⁷⁷Lu]Lu)₈-LA₄. These MCPs form mono-thiol, di-thiol or multi-thiol bonds with AuNPs, respectively (Yook et al. 2016b). Dissociation of these polymers from AuNPs in the presence of the reducing agent, dithiothreitol (DTT) or Cys or GSH causes aggregation which results in a change in the spectroscopic properties of the AuNPs, which was used to assess the relative stability of the gold-thiol bonds. A multi-thiol linkage was the most stable in vitro to DTT, Cys or GSH challenge and to incubation in human plasma. AuNPs conjugated to PEG_2K-pGlu(DOTA-[¹⁷⁷Lu]Lu)₈-LA₄ resulted in the lowest liver uptake in vivo in non-tumour bearing athymic mice, but higher spleen uptake was noted compared to di-thiol MCPs. Thus, gold-thiol conjugation enabled by LA-functionalized polymers was used by our team to construct all subsequent radiation nanomedicines.

We then constructed dual receptor-targeted (DRT) radiation nanomedicines that bind both HER2 and EGFR by conjugating trastuzumab-PEG_5K-LA and panitumumab-PEG_5K-LA and [¹⁷⁷Lu]Lu-DOTA-PEG_3K-LA to AuNPs (Yook et al. 2020) (Fig. 6a). These DRT radiation nanomedicines were intended to overcome receptor heterogeneity in BC tumours and exploit the co-expression of HER2 and EGFR by some trastuzumab-resistant BC cells (Gallardo et al. 2012). Single receptor-targeted (SRT) radiation nanomedicines were synthesized by conjugating only trastuzumab-PEG_5K-LA or panitumumab-PEG_5K-LA and [¹⁷⁷Lu]Lu-DOTA-PEG_3K-LA to AuNPs. DRT and SRT radiation nanomedicines were compared for binding and internalization into MDA-MB-231/H2N human BC cells that co-expressed moderate levels of HER2 and EGFR (HER2^mod/EGFR^mod), MDA-MB-468 cells cells with high levels of EGFR but negligible HER2 (EGFR^high/HER2^neg) or BT-474 cells with high HER2 but low EGFR (HER2^high/EGFR^low). Darkfield microscopy and cell binding assays (Fig. 6b) revealed that DRT radiation nanomedicines were bound by MDA-MB-231/H2N cells expressing both EGFR and HER2, while SRT forms were bound only by BC cells that displayed either EGFR or HER2. DRT were more effective in vitro than SRT radiation nanomedicines for decreasing the CS of MDA-MB-231/H2N cells that co-expressed HER2 and EGFR (Fig. 6c). Non-targeted radiation nanomedicines were less cytotoxic in vitro than either DRT or SRT forms. In the next section, we discuss the landscape of NPs labeled with β-particle emitting radionuclides for cancer treatment.

Landscape: NPs labeled with β-particle emitting radionuclides

Lutetium-177

Gold nanoparticles (AuNPs)

Mendoza-Nava et al. (2017) synthesized dual-targeted ¹⁷⁷Lu-labeled AuNPs that bound both the folate receptor-α (FR-α) and gastrin-releasing peptide receptor (GRPR). Poly(amidoamine) (G4 PAMAM) dendrimers were conjugated to folic acid and bombesin to target these receptors, respectively. The dendrimers were derivatized with p-SCN-benzyl-DOTA (Bn-DOTA) to complex ¹⁷⁷Lu. These dendrimers were incorporated into the synthesis reaction of AuNPs. The resulting radiation nanomedicines were intended to enable combined hyperthermia and radiation treatment of BC. Hyperthermia is mediated by absorption of near infrared (nIR) light by AuNPs (Beik et al. 2016). Applying laser light at 532 nm (1.19 W/cm²) to T47D human BC cells that bound these AuNPs raised their temperature from 39.1 to 46.8 °C, and decreased their CS in vitro by > 85%. Moreover, [¹⁷⁷Lu]Lu-Bn-DOTA-dendrimer-folic/acid-bombesin-AuNPs were fourfold more cytotoxic than non-targeted [¹⁷⁷Lu]Lu-Bn-DOTA-dendrimer-AuNPs, decreasing the CS of T47D cells by > 90%, in agreement with the fourfold higher absorbed dose (63 Gy vs. 15 Gy, respectively).

Vilchis-Juarez et al. (2014) constructed AuNPs modified with cyclic arginine-glycine-aspartic acid (cRGD) peptides to target α_vβ₃ integrins and conjugated these AuNPs to [¹⁷⁷Lu]Lu-DOTA-GGC peptides. The size and charge of the [¹⁷⁷Lu]Lu-DOTA-GGC-AuNPs-cRGD were 26 nm and − 64.6 mV, respectively. Intratumoural (i.t.) injection of 4 weekly amounts (2 MBq) of [¹⁷⁷Lu]Lu-DOTA-GGC-AuNPs-cRGD in athymic mice with s.c. human C6 glioma xenografts decreased tumour volumes by 27-fold at 23 d compared to untreated mice. [¹⁷⁷Lu]Lu-DOTA-GGC-AuNPs-cRGD targeting α_vβ₃ integrins on C5 tumour cells were threefold more effective than non-targeted [¹⁷⁷Lu]Lu-DOTA-GGC-AuNPs. Intratumoural (i.t.) injection resulted in high and retained ¹⁷⁷Lu activity in the tumour. This deposited high absorbed doses in the tumour (64 Gy) but only low doses (< 1 Gy) in kidneys, liver and spleen. No kidney toxicity was detected. Interestingly, treatment of C6 tumours with [¹⁷⁷Lu]Lu-DOTA-GGC-AuNPs-cRGD resulted in a decrease in the tumour uptake of [¹⁸F]F-2-fluorodeoxyglucose ([¹⁸F]FDG) compared to untreated mice, indicating a metabolic response to these radiation nanomedicines. In addition, tumour vascular endothelial growth factor (VEGF) gene expression was decreased, suggesting that [¹⁷⁷Lu]Lu-DOTA-GGC-AuNPs-cRGD may have anti-angiogenic properties. The advantage of i.t. injection of these radiation nanomedicines is clearly shown by comparing these results to a previous report (Luna-Gutierrez et al. 2012) which found that the absorbed dose in s.c. U87MG human glioma tumours in mice after intraperitoneal (i.p.) administration of ¹⁷⁷Lu-labeled AuNPs modified with RGD peptides to target α_vβ₃ integrins was only 0.1–0.36 Gy, due to much lower tumour uptake, likely as a result of liver and spleen sequestration.

Micelles, polymers and dendrimers

PEGylated liposomes (100–116 nm) were synthesized by Petersen et al. (2016) that trapped DOTA for complexing ⁶⁴Cu or ¹⁷⁷Lu. This study focused on PET imaging with i.v. injected [⁶⁴Cu]Cu-DOTA-liposomes to evaluate different levels of PEGylation (10 mol% vs. 5 mol%) on the tumour and normal tissue uptake in mice bearing s.c. H727 human neuroendocrine tumour xenografts. Tumour uptake ranged from 5 to 6% ID/g at 48 h p.i., and was maximized for 10 mol% PEGylation. Tumour doses were 0.11 Gy/MBq for small (2 g) tumours and 0.011 Gy/MBq for larger (20 g) tumours. These absorbed doses are very low compared to studies of ¹⁷⁷Lu-labeled NPs administered by i.t. injection as discussed previously. Spleen and liver uptake were high (15–16% ID/g and 10–11% ID/g at 48 h p.i., respectively). The liver and spleen were among the normal organs receiving the highest radiation absorbed doses. Wang et al. (2020a) synthesized DOTA-tri-arginine-lipid micelles as a cationic cell-penetrating liquid form of brachytherapy labeled with ¹⁷⁷Lu for treating tumours or with ⁶⁴Cu for PET imaging. Retention in s.c. CT26 murine colon carcinoma tumours in Balb/c mice after i.t. injection of these [⁶⁴Cu]Cu-DOTA-tri-arginine-lipid micelles was assessed. While i.t. injected [⁶⁴Cu]CuCl₂ or [⁶⁴Cu]Cu-DOTA were rapidly eliminated from the tumour (< 10% ID/g remaining at 24 h), [⁶⁴Cu]Cu-DOTA-tri-arginine-lipid micelles were cleared more slowly with 34% ID/g remaining at 6 h and 28% ID/g at 24 h p.i., suggesting the effects of cell-penetration mediated by the tri-arginine peptide.

Shi et al. (2021) synthesized semiconducting polymer nanoparticles (SPNs; ~ 207 nm) that absorb near infrared (nIR) light and enable photothermal therapy (PTT). These SPNs were modified with DOTA for complexing ¹⁷⁷Lu and with glucose-dependent insulinotropic polypeptide (GIP) for targeting pancreatic cancer. Treatment of CFPAC human pancreatic cancer cells in vitro with these [¹⁷⁷Lu]Lu-DOTA-GIP-SPNs (0.37–11.1 MBq/mL) combined with PTT by irradiation with a 808 nm laser (1 W cm⁻², 5 min) reduced cell viability in a concentration-dependent manner to as low as 4.4%, while treatment with the highest concentration of [¹⁷⁷Lu]Lu-DOTA-GIP-SPNs, only reduced cell viability to 34%. Non-radioactive DOTA-GIP-SPNs were not cytotoxic. In mice with s.c. CFPAC tumours, i.t. injection of [¹⁷⁷Lu]Lu-DOTA-GIP-SPNs retained ¹⁷⁷Lu activity in the tumour with no visible uptake in normal tissues by SPECT/CT. Treatment of mice with s.c. CFPAC tumours with 1.1 MBq of [¹⁷⁷Lu]Lu-DOTA-GIP-SPNs injected i.t. combined with PTT arrested tumour growth, while [¹⁷⁷Lu]Lu-DOTA-GIP-SPNs or PTT alone only slowed tumour growth compared to mice treated with non-radioactive DOTA-GIP-SPNs with or without PTT or normal saline-treated mice. These results are promising for local treatment of pancreatic cancer and suggest that combining PTT and ¹⁷⁷Lu]Lu-DOTA-GIP-SPNs may be the most effective approach.

Hosseini et al. (2023) modified G4 PAMAM dendrimers with cetuximab for targeting EGFR and CHX-diethylenetriaminepentaacetic acid (CHX-DTPA) to complex ¹⁷⁷Lu. G4 PAMAM dendrimers were relatively non-cytotoxic to EGFR-positive SW-480 human colon cancer cells in vitro, but conjugation of dendrimers to cetuxumab and especially, labeling with ¹⁷⁷Lu increased cytotoxic potency. SPECT imaging in mice with s.c. SW-480 tumours showed tumour uptake at 24 h post i.v. injection. Tumour uptake was highest at 24 h p.i. (12% ID/g) but liver uptake was almost as high (11% ID/g). There was lower uptake in the spleen (2% ID/g) and kidneys (1% ID/g). No treatment or toxicity studies were performed.

Cellulose nanocrystals

Imlimthan et al. (2021) functionalized cellulose nanocrystals (CNCs) with DOTA for complexing ¹⁷⁷Lu and poly-L-lysine to enable binding of the BRAF inhibitor, vemurafenib via electrostatic interaction to the CNCs. [¹⁷⁷Lu]Lu-DOTA-verafenib-CNCs were cytotoxic in vitro to YUMM1.G1 and A375 melanoma cells in clonogenic assays. Biodistribution studies in mice with YUMM1.G1 tumours after i.v. injection of [¹⁷⁷Lu]Lu-DOTA-verafenib-CNCs showed high but transient uptake in metastatic lungs reaching 47% ID/g at 6 h but decreasing to 18% ID/g at 72 h p.i. Liver and spleen uptake were high (18–26% ID/g and 28–60% ID/g, respectively). Treatment of mice with YUMM1.G1 lung metastases with two amounts (2 MBq) of [¹⁷⁷Lu]Lu-DOTA-verafenib-CNCs separated by 10 days improved median survival to 27 d vs. 17 d for [¹⁷⁷Lu]Lu-DOTA-CNCs not bound to vemurafenib and 13 d for vemurafenib alone or 12 d for vehicle-treated mice. However, fatal secondary metastases formed in the cardiac muscle and thoracic cavity that could not be effectively treated, which would prevent further development of these NPs.

Inorganic NPs

Salvanou et al. (2022) constructed calcium alginate and PEGylated magnetic iron oxide NPs (MIONPs; ~ 120 nm) and labeled these to high efficiency (90–95%) by direct binding of ¹⁷⁷Lu or ⁶⁸Ga in Na acetate buffer, pH 5.5 or 4.0, respectively, heated at 75 °C for 30 min. ¹⁷⁷Lu or ⁶⁸Ga-labeled MIONPs were relatively stable in serum (> 70% up 7 d at 37 °C). Non-radioactive MIONPs were not cytotoxic to 4T1 murine mammary carcinoma cells in vitro, but ¹⁷⁷Lu-labeled MIONPs (4 MBq/mL) modestly decreased cell proliferation. Biodistribution was studied only in healthy mice but there was high uptake in the liver (20–27% ID/g) and spleen (10–13% ID/g) after i.v. injection. No in vivo treatment studies were conducted. Stankovic et al. (2023) constructed superparamagnetic iron oxide NPs (SPIONs; ~ 11 nm) coated with dimercaptosuccinic acid (DMSA) which were labeled to high efficiency (86%) with ¹⁷⁷Lu. These [¹⁷⁷Lu]Lu-DMSA-SPIONs were stable in vitro in serum up to 6 d at 37 °C. Following i.t. injection in Balb/c mice with s.c. CT26 or 4T1 tumours, uptake in these tumours was high and strongly retained (> 95%) up to 11 d p.i. Similar to other studies that used i.t. injection of radiolabeled NPs, there was minimal uptake (< 1% ID/organ) in the liver, kidneys, spleen or lungs. However, in mice with 4T1 tumours, liver uptake increased to 19.8% ID/organ, then subsequently decreased to 4.3% ID/organ at 14 d.i. Administration of a single amount (3.7 MBq) of [¹⁷⁷Lu]Lu-DMSA-SPIONs in mice with 4T1 or CT26 tumours slowed tumour growth compared to mice treated with non-radioactive DMSA-SPIONs or untreated mice, but did not arrest the growth or decrease the size of these tumours. A second administration after 5 d did not improve tumour response. Similar tumour growth inhibition was observed for a range of administered activity (1.85–9.25 MBq) of [¹⁷⁷Lu]Lu-DMSA-SPIONs. Histopathological staining showed slight toxicity to the liver and kidneys.

Zhang et al. (2020) synthesized PEGylated silica NPs (~ 6 nm) modified with α-melanocyte stimulating hormone (α-MSH) peptides to target melanocortin-1 receptors on melanoma cells. These NPs were conjugated to DOTA and efficiently (> 95%) complexed ¹⁷⁷Lu. [¹⁷⁷Lu]Lu-DOTA-α-MSH-NPs were stable (> 90%) in vitro in serum up to 24 h at 37 °C. [¹⁷⁷Lu]Lu-DOTA-α-MSH-NPs were bound and internalized in vitro by B16F10 and M21 melanoma cells. In SCID mice with s.c. B16F10 tumours or C57BL6 mice with M21 tumours, tumour uptake at 24 h post i.v. injection was 9.6% ID/g and 9.3% ID/g, respectively. In SCID mice, liver and spleen uptake were low (5.8% ID/g and 5.1% ID/g, respectively) but in C57BL6 mice, uptake in these organs was 1.5-fold higher. [¹⁷⁷Lu]Lu-DOTA-α-MSH-NPs were eliminated mainly by renal excretion with almost 80% excreted in the urine by 96 h p.i. Dosimetry showed that the kidneys received the highest absorbed doses (3.8 cGy/37 MBq) but bone marrow and intestine doses were low (0.12 cGy/37 MBq). The MTD in mice was 37 MBq based on loss of body weight. Treatment of mice with s.c. M21 tumours with 18.5 or 37 MBq of [¹⁷⁷Lu]Lu-DOTA-α-MSH-NPs administered i.v. increased median survival to 58 and 43 d, respectively, compared to mice treated with non-radiolabeled NPs (41 d) or no treatment (27 d). Administration of 18.5 or 37 MBq of non-targeted [¹⁷⁷Lu]Lu-DOTA-NPs increased median survival to 33 d or 60 d, respectively. In this case, tumour uptake was most likely mediated by the EPR effect. Treatment of mice with B16F10 tumours with 18.5 MBq of [¹⁷⁷Lu]Lu-DOTA-α-MSH-NPs increased the median survival to 25 d versus 21 d for non-targeted [¹⁷⁷Lu]Lu-DOTA-NPs, 14 d for non-radioactive NPs, or 16 d for untreated mice.

Neutron-activated lutetium oxide NPs

An interesting approach to construction of radiation nanomedicines was reported by Ancira-Cortez et al. (2020). Stable lutetium oxide (^NatLu₂O₃) NPs (~ 27 nm) were synthesized, then neutron-activated in a reactor (1 × 10¹³ n sec⁻¹ cm⁻² for 20 h) to produce [¹⁷⁷Lu]Lu₂O₃ NPs. These NPs were then modified with prostate-specific membrane antigen (PSMA)-binding peptides by reaction with DOTA-HYNIC-iPSMA through the DOTA moiety which complexes lutetium. The [¹⁷⁷Lu]Lu₂O₃-DOTA-HYNIC-iPSMA NPs were specifically bound and internalized in vitro by PSMA-positive HepG2 human hepatocellular carcinoma cells, and reduced their viability to 53% versus 69% for non-targeted [¹⁷⁷Lu]Lu₂O₃ NPs. The cytotoxicity of non-targeted NPs was explained by non-specific uptake by HepG2 cells combined with the cross-fire effect of the 2 mm range β-particles emitted by ¹⁷⁷Lu. At 24 h post i.v. injection in healthy Balb/c mice, the [¹⁷⁷Lu]Lu₂O₃-DOTA-HYNIC-iPSMA NPs localized in the liver (9% ID/g) with lower uptake in the spleen (0.8% ID/g) and kidneys (0.7% ID/g). Interesting images were obtained showing the liver uptake of these [¹⁷⁷Lu]Lu₂O₃-DOTA-HYNIC-iPSMA NPs, by taking advantage of the luminescence of ^NatLu₂O₃ when exposed to the β-particle and γ-photon emissions of ¹⁷⁷Lu. In a subsequent report (Luna-Gutierrez et al. 2022), stable ^NatLu₂O₃ NPs were neutron-activated to [¹⁷⁷Lu]Lu₂O₃ NPs in a nuclear reactor, then modified with DOTA-HYNIC-iPSMA or an inhibitor of fibroblast activation protein ligand (DOTA-HYNIC-iFAP). Intratumoural (i.t.) injection of these [¹⁷⁷Lu]Lu₂O₃-DOTA-HYNIC-iPSMA or [¹⁷⁷Lu]Lu₂O₃-DOTA-HYNIC-iFAP NPs in mice with s.c. HCT116 human colon cancer xenografts resulted in very high tumor uptake that was retained up to 96 h p.i. (77–84% ID/g) with minimal uptake in the liver (~ 1% ID/g) or spleen (< 0.5% ID/g). Mice treated with 1–2 MBq of [¹⁷⁷Lu]Lu₂O₃-DOTA-HYNIC-iPSMA or [¹⁷⁷Lu]Lu₂O₃-DOTA-HYNIC-iFAP NPs showed strong tumor growth inhibition compared to untreated mice. Non-targeted [¹⁷⁷Lu]Lu₂O₃ NPs also inhibited tumor growth but were less effective than the targeted NPs. There was no liver or kidney toxicity observed. The absorbed doses in the tumour were very high (> 100 Gy). These results are very promising for application of [¹⁷⁷Lu]Lu₂O₃-DOTA-HYNIC-iPSMA or [¹⁷⁷Lu]Lu₂O₃-DOTA-HYNIC-iFAP NPs for local treatment of tumours expressing PSMA or FAP. Particularly fascinating was that this report included a first-in-human study of a patient with widespread unresectable liver metastases from colon cancer who was administered 185 MBq of [¹⁷⁷Lu]Lu₂O₃-DOTA-HYNIC-iPSMA NPs by i.v. injection. SPECT/CT imaging demonstrated uptake of [¹⁷⁷Lu]Lu₂O₃-DOTA-HYNIC-iPSMA NPs in liver metastases, which were further identified as PSMA-positive by SPECT imaging with [^99mTc]Tc-iPSMA. Although in this human study the radiation nanomedicine was administered i.v., based on dosimetry calculations, it was estimated that up to 1,350 MBq could be safely administered to humans without exceeding the tolerable doses in normal organs, and this administered amount may deposit 42–202 Gy in liver metastases.

Rhenium-186

Rhenium-186 [¹⁸⁶Re; half-life (t_1/2) = 3.8 d] decays by β-particle emission (E_βmax = 1.09 MeV; 92.5%) to stable osmium-186 (¹⁸⁶Os) or by electron capture (EC) to tungsten-186 (¹⁸⁶W; 7.5%) with emission of a γ-photon (Eγ = 136 keV) that allows SPECT imaging. Soundararajan et al. (Soundararajan et al. 2011) complexed ¹⁸⁶Re to N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA) chelators that were incorporated into Dox-containing liposomes. They also synthesized ¹⁸⁶Re-labeled PEGylated liposomes without Dox. The MTD in nude rats after i.v. administration was 740 MBq/kg for [¹⁸⁶Re]Re-BMEDA-Dox liposomes and 1,480 MBq/kg for [¹⁸⁶Re]Re-BMEDA-PEG-liposomes, due to dose-limiting hematopoietic toxicity, which recovered at 28 d p.i. Additionally, the [¹⁸⁶Re]Re-BMEDA-Dox liposomes caused gastrointestinal toxicity. Treatment of nude rats with s.c. head and neck squamous cell carcinoma (SCC-4) tumours at the MTD slowed tumour growth. [¹⁸⁶Re]Re-BMEDA-Dox liposomes were more effective than [¹⁸⁶Re]Re-BMEDA-PEG-liposomes. At the MTD, the absorbed doses in the tumour for [¹⁸⁶Re]Re-BMEDA-Dox liposomes and [¹⁸⁶Re]Re-BMEDA-PEG-liposomes were 46 Gy and 32 Gy, respectively. Normal organ doses were 68 Gy, 38 Gy and 288 Gy for the lungs, liver and kidneys, respectively in rats injected with [¹⁸⁶Re]Re-BMEDA-Dox liposomes and 57 Gy, 71 Gy and 425 Gy for rats receiving [¹⁸⁶Re]Re-BMEDA-PEG-liposomes. Thus, although these results suggest that a combined chemoradiation therapy approach may be promising for treating tumours, there were high normal organ absorbed doses and normal tissue toxicity for these i.v. administered radiation nanomedicines. To improve their safety and dosimetry, Hyrcushko et al. (2011) instead intratumorally (i.t.) infused [¹⁸⁶Re]Re-BMEDA-PEG-liposomes in nude rats with s.c. SCC-4 tumours and estimated the absorbed doses in tumours for correlation with response to treatment. A single i.t. infusion (185 MBq/cm³ of tumour) or three fractionated i.t. infusions to more evenly space activity distribution in the tumour, as well as i.p. injection of anti-vascular endothelial growth factor (VEGF) bevacizumab (Avastin^®; Genentech) prior to infusion of the [¹⁸⁶Re]Re-BMEDA-PEG-liposomes were studied. Multiple fractionated infusions improved tumour dose homogeneity and bevacizumab improved retention of [¹⁸⁶Re]Re-BMEDA-liposomes in the tumour by disrupting tumour vascularization. No correlation was found between overall tumour dose and response, but the Equivalent Uniform Dose (EUD) which assessed the tumour dose heterogeneity predicted tumour response. In a follow-up study, French et al. (2010) examined the effectiveness of [¹⁸⁶Re]Re-BMEDA-PEG-liposomes infused i.t. in three fractionated amounts (total = 185 MBq/cm³ of tumour) for treatment of s.c. SCC-4 tumours in nude rats. Tumour growth was strongly inhibited for rats infused i.t. with [¹⁸⁶Re]Re-BMEDA-PEG-liposomes, while rats receiving unlabeled liposomes or non-liposomal [¹⁸⁶Re]Re-perrhenate or [¹⁸⁶Re]Re-BMEDA showed rapid tumour growth. In rats infused with [¹⁸⁶Re]Re-BMEDA-PEG-liposomes, tumour activity was 48% ID/g after i.t. infusion but this decreased to 9% ID/g at 140 h p.i. However, non-liposomal [¹⁸⁶Re]Re-sodium perrhenate and [¹⁸⁶Re]Re-BMEDA were rapidly eliminated from the tumour in 2–4 h. Absorbed doses in the tumour were high (526 Gy). [¹⁸⁶Re]Re-BMEDA-PEG-liposomes were not toxic to normal tissues, causing only a minor decrease in body weight and no evidence of hematopoietic toxicity. This study further highlights the major advantages of i.t. administration of radiation nanomedicines for improving their effectiveness for treating tumours and ability to minimize normal organ doses and toxicity.

Rhenium-188

¹⁸⁸Re (t_1/2 = 16.9 h) decays to ¹⁸⁸Os by β-particle emission (Eβmax = 2.12 MeV; 85%) and emits a γ-photon [Eγ = 155 keV (15%)] that allows SPECT imaging. Liu et al. (2012) synthesized [¹⁸⁸Re]Re-BMEDA-PEG-liposomes and compared their effectiveness after i.v. injection to liposomal Dox (Lipo-Dox) for treating 4T1 murine mammary carcinoma tumours in Balb/c mice. SPECT/CT and biodistribution studies were used to assess tumour and normal tissue uptake of [¹⁸⁸Re]Re-BMEDA-PEG-liposomes. Maximum tumour uptake occurred at 24 h p.i. (3.0% ID/g) but there was high liver (4.6% ID/g) and spleen (3.0% ID/g) uptake at this time point, and excretion in the feces (4.7% ID/g). The MTD for [¹⁸⁸Re]Re-BMEDA-PEG-liposomes was 37 MBq and for Lipo-Dox was 25 mg/kg, but the MTD was identified based on body weight loss or treatment-induced death, and did not assess blood cell counts or serum biochemistry. SPECT/CT showed tumour uptake and uptake in the liver and spleen. Lipo-Dox (20 mg/kg) was most effective for decreasing the growth of small (~ 50 mm³) and large (~ 300 mm³) 4T1 tumours and for prolonging survival. [¹⁸⁸Re]Re-BMEDA-PEG-liposomes (29.6 MBq) slowed tumour growth compared to untreated mice and slightly to modestly improved survival.

[¹⁸⁸Re]Re-BMEDA-PEG-DXR-liposomes, where DXR is doxorubicin, were studied for treatment of s.c. CT26 tumours in Balb/c mice after i.v. injection of three amounts (22.2 MBq) separated by 4 d (Chang et al. 2010). Peak tumour uptake occurred at 24 h p.i. (6.1% ID/g). At this time point, spleen uptake was high (20.2% ID/g) but liver uptake (5.9% ID/g) and kidney uptake (3.3% ID/g) were lower. Tumour size decreased by treatment with [¹⁸⁸Re]Re-BMEDA-PEG-DXR-liposomes and tumours were growth-arrested by [¹⁸⁸Re]Re-BMEDA-PEG-liposomes without Dox. Tumour growth was inhibited by Lipo-Dox compared to normal saline treated mice, but this was less effective than the ¹⁸⁸Re-labeled liposomes. [¹⁸⁸Re]Re-BMEDA-PEG-DXR-liposomes were the most effective for prolonging survival, followed by [¹⁸⁸Re]Re-BMEDA-PEG-liposomes while Lipo-Dox did not significantly improve survival compared to normal saline-treated mice. Tsai et al. (2011) studied the biodistribution and pharmacokinetics of [¹⁸⁸Re]Re-BMEDA-PEG-liposomes and compared their effectiveness to 5-fluorouracil (5-FU) for treating C26 murine colon carcinoma peritoneal metatastases after i.v. injection in Balb/c mice. Blood activity decreased from 41 to 1.4% ID/g over 72 h. Uptake in metastases was maximal at 16–24 h p.i. (7.4–7.9% ID/g). The highest normal tissue uptake at these time points was in the liver (5.2–6.6% ID/g), spleen (7.5–7.6% ID/g) and kidneys (4.2–5.0% ID/g). SPECT imaging showed localization of [¹⁸⁸Re]Re-BMEDA-PEG-liposomes in metastases in the peritoneal cavity. Based on body weight loss, the MTD for [¹⁸⁸Re]Re-BMEDA-PEG-liposomes was 37 MBq. Encouragingly, a single administration of [¹⁸⁸Re]Re-BMEDA-PEG-liposomes at 80% of the MTD (29.6 MBq) prolonged survival of mice with peritoneal metastases (32.8 d) compared to mice treated with 5-FU (26.7 d) or receiving no treatment (24.3 d). Chen et al. (2008) studied local intraperitonal (i.p.) injection of [¹⁸⁸Re]Re-BMEDA-PEG-DXR-liposomes co-loaded with Dox for treatment of peritoneal C26 tumours in Balb/c mice. These tumours form ascites. ¹⁸⁸Re activity in the ascites decreased from 49 to 3.9% ID/g at 96 h p.i. Tumour uptake was maximal at 48 h p.i. (1.9% ID/g). Spleen uptake at 48 h p.i. was very high (31.2% ID/g) but liver and kidney uptake were lower (5.2% ID/g and 2.0% ID/g, respectively). The MTD of [¹⁸⁸Re]Re-BMEDA-PEG-DXR-liposomes based on body weight loss and a transient decrease in WBC and platelet counts at 1–2 weeks post-treatment was 29.6 MBq. Treatment of tumour-bearing mice with 22.2 MBq of [¹⁸⁸Re]Re-BMEDA-PEG-DXR-liposomes was more effective than [¹⁸⁸Re]Re-BMEDA-PEG-liposomes or Lipo-Dox for prolonging survival (29.3 d vs. 23.2 d and 22.2 d, respectively). In another study, lung metastases from CT26 colon cancer tumours in Balb/c mice were treated by i.v. injection of 29.6 MBq of [¹⁸⁸Re]Re-BMEDA-PEG-liposomes (Chen et al. 2012). The median survival of these mice increased to 58 d versus 42–43 d for mice treated with unlabeled liposomes or normal saline. Treatment with 5-FU was less effective (median survival = 49 d). Tumour uptake reached 5.5% ID/g at 24 h and uptake in the spleen, liver and kidneys at this time point were 6.9% ID/g, 8.2% ID/g and 4.4% ID/g, respectively. The advantage of local i.p. vs. i.v. administration of [¹⁸⁸Re]Re-BMEDA-PEG-liposomes was further demonstrated in mice with intraperitoneal ES-2 human ovarian cancer tumours (Shen et al. 2016). These tumours were radiation-resistant and expressed cancer stem cell (CSC) biomarkers (CD44^high/CD24^high/CD133^high). Treatment with [¹⁸⁸Re]Re-BMEDA-PEG-liposomes at one third the MTD administered i.v. was not effective, but i.p. administration controlled tumour growth in the peritoneum assessed by bioluminescence imaging (BLI) and prolonged survival compared to untreated mice. Moreover, i.p. [¹⁸⁸Re]Re-BMEDA-PEG-liposomes reversed the glycolytic stem cell phenotype of these cells back to oxidative phosphorylation and decreased expression of CSC biomarkers on tumour cells.

Yttrium-90

⁹⁰Y (t_1/2 = 64 h) decays to ⁹⁰Zr by β-particle emission (E_βmax = 2.2 MeV; 100%) but does not emit a γ-photon, thus imaging is limited to detecting the Bremsstrahlung radiation resulting from interaction of β-radiation with tissues, which has poor spatial resolution. Radovic et al. (2015) constructed spherical iron oxide (Fe₂O₃) nanoparticles (IONPs) that were not modified with PEG (naked; 80 nm) or were PEGylated (46 nm) and further incorporated ⁹⁰Y. The aim was to synthesize multi-functional IONPs that may be used for combined magnetic hyperthermia and radiotherapy. After i.v. injection in rats, there was high liver uptake of naked and PEGylated [⁹⁰Y]Y-IONPs, but the lung uptake was sixfold higher for naked [⁹⁰Y]Y-IONPs. No studies were performed to examine their therapeutic potential. Ognjanovic et al. (2019) synthesized IONPs with a “flowerlike” structure and labeled these with ⁹⁰Y, ¹⁷⁷Lu or ^99mTc to a high efficiency (> 97%). Magnetic hyperthermia with unlabeled IONPs killed mouse CT-26 colon cancer cells, but without magnetic hyperthermia there was no cytotoxicity. The effects of the radiation emitted by ⁹⁰Y, ¹⁷⁷Lu or ^99mTc on CT-26 cells were not studied. However, in a subsequent report, Vukadinovic et al. (2022) evaluated the tumour growth inhibitory effects of these [⁹⁰Y]Y-IONPs after i.t. injection in mice with s.c. CT-26 or 4T1 murine mammary carcinoma tumours combined with magnetic hyperthermia. Intratumoral (i.t.) injection of 1.85 MBq [⁹⁰Y]Y-IONPs alone or combined with magnetic hyperthermia inhibited tumour growth. In contrast, i.v. administration of these [⁹⁰Y]Y-IONPs resulted in low tumour uptake that was not considered feasible for therapy studies. Guryev et al. (2018) constructed NPs (~ 50 nm) composed of a sodium yttrium fluoride (NaYF₄) core that incorporated Na[⁹⁰Y]YF₄ surrounded by a shell of ytterbium (Yb), thulium (Tm) and NaYF₄. These NPs were then conjugated to Pseudomonas Exotoxin (PE40) fused to a designed ankyrin repeat protein (DARPin) that binds HER2. These targeted Na[⁹⁰Y]YF4 NPs were cytotoxic in vitro to HER2-positive SK-BR-3 human BC cells and inhibited the growth of SK-BR-3 tumour xenografts in vivo in athymic mice. Our team has studied ⁹⁰Y-labeled AuNPs incorporated into a nanoparticle depot (nanodepot; NPD) for local treatment of 4T1 murine mammary carcinoma tumours in mice (see subsequent Scientific Journey section: Nanodepot for i.t. delivery of ⁹⁰Y-labeled NPs).

Gold-198

¹⁹⁸Au decays (t_1/2 = 2.7 d) decays to stable ¹⁹⁸Hg by β-particle emission (Eβmax = 0.96 MeV; 99%) and emits a γ-photon [Eγ = 411 keV (96%)] that may be imaged by SPECT. ¹⁹⁸Au is attractive for synthesizing radiation nanomedicines because it may be incorporated directly into AuNPs and does not require conjugating metal-chelating polymers for radiolabeling. This makes ¹⁹⁸AuNPs easy to synthesize and stable, since they are more resistant to loss of radiometal. Nonetheless, taking a different synthetic approach, Xuan et al. (2020) produced ¹⁹⁸Au gold nanoclusters (¹⁹⁸AuNCs) by neutron irradiation of stable [¹⁹⁷Au]AuNCs in a nuclear reactor using the ¹⁹⁷Au(n, γ)¹⁹⁸Au reaction. The cytotoxicity of these ¹⁹⁸AuNCs was assessed in vitro on human PC-3 pancreatic cancer cells, MDA-MB-231 human breast cancer (BC) cells and MV3 melanoma cells. At absorbed doses of 2 Gy and 4 Gy, ¹⁹⁸AuNCs were as cytotoxic as 100 nM paclitaxel against all three cell lines. No in vivo therapeutic studies were performed. Black et al. (2014) synthesized different shapes (spheres, disks, rods and cages) of PEGylated AuNPs incorporating ¹⁹⁸Au that each had a similar size (~ 50 nm) and studied their tumour and normal tissue uptake after i.v. injection in mice with s.c. EMT6 murine mammary carcinoma tumours. Spherical ¹⁹⁸AuNPs exhibited the longest residence time in the blood, while other shapes of ¹⁹⁸AuNPs were cleared quickly from the blood. Spleen uptake of spherical ¹⁹⁸AuNPs was only ~ 6% ID/g at 24 h p.i., but was much greater (50–100% ID/g) for other shapes. Liver uptake was high for spherical ¹⁹⁸AuNPs (~ 50% ID/g) but was even higher for disk, rod or cage-shaped ¹⁹⁸AuNPs. Interestingly, Cerenkov radiation caused by interaction of the β-particles emitted by ¹⁹⁸Au with tissues was used to image the tumour and normal organ uptake of ¹⁹⁸AuNPs. Unusually high tumour uptake for i.v. administration was found for spherical ¹⁹⁸AuNPs (23.2% ID/g at 24 h p.i.), but this was lower for disks (4.9%ID/g), rods (< 2.0% ID/g) or cages (7.5% ID/g). The results of this study suggest that spherical AuNPs may be best suited to construct radiation nanomedicines.

Other β-particle emitting radionuclides

Kao et al. (2013) conjugated PEGylated AuNPs (53 nm) to ¹²³I/¹³¹I-labeled anti-EGFR C225 mAbs. ¹³¹I (t_1/2 = 8 d) decays to ¹³¹Xe, emitting β-particles [E_βmax = 0.60 MeV (89.9%) and 0.33 MeV (7.3%)] and an imageable γ-photon [Eγ = 364 keV (82%)]. ¹²³I (t_1/2 = 13.2 h) is an AE-emitter that decays by EC to ¹²³Te emitting a γ-photon [Eγ = 159 keV (83.2%)] for SPECT imaging. Confocal fluorescence microscopy revealed that C225-PEG-AuNPs were bound and internalized into EGFR-positive A431 human lung cancer cells in vitro. Using a cell-proliferation assay, it was found that [¹³¹I]I-C225-PEG-AuNPs reduced the viability of A431 cells to ~ 37% versus 82% for treatment with free ¹³¹I. A431 tumors were imaged by SPECT in mice up to 4 h post-i.v. injection, but tumour activity was cleared by 8 h p.i. There was high liver and spleen uptake.

Journey: nanoparticle depot for i.t. delivery of ⁹⁰Y-labeled NPs

Although i.t. injection of radiation nanomedicines offers major advantages in maximizing the uptake and retention of activity in tumours and minimizing normal tissue uptake yielding high absorbed doses in tumours with low doses in normal organs, direct i.t. injection results in unpredictable and heterogeneous distribution of activity and consequently heterogeneous dose distribution. For example, we found that i.t. injection of 4.5 MBq of EGFR-targeted [¹⁷⁷Lu]Lu-DOTA-PEG_4K(panitumumabPEG_5K)-AuNPs or non-targeted [¹⁷⁷Lu]Lu-DOTA-PEG_4K-AuNPs into s.c. MDA-MB-468 tumours in mice resulted in wide radioactivity distribution ranging from 0 to 2750 Bq and 0–400 Bq, respectively (Yook et al. 2016a). Although the maximum 2 mm penetration of the β-particles emitted by ¹⁷⁷Lu mitigates the heterogeneity in dose distribution by a “cross-fire” effect, the absorbed doses distribution were also wide and ranged from 0–1300 Gy for [¹⁷⁷Lu]Lu-DOTA-PEG_4K(panitumumab-PEG_5K)-AuNPs and 0–250 Gy for [¹⁷⁷Lu]Lu-DOTA-PEG_4K-AuNPs. For clinical application of radiation nanomedicines, it is important to have predictable, homogeneous, and sufficiently high absorbed doses in the tumour to assure that a minimum dose is received in all regions to cause several logarithms of tumour cell killing. Thus, in the next step in our journey, we constructed a nanoparticle depot (NPD) that incorporated radiolabeled AuNPs and could be precisely inserted into tumours utilizing clinically-used brachytherapy seed needle insertion techniques to achieve predictable dose delivery (Lai et al. 2016) (Fig. 7a) The NPD dimensions (0.8 mm × 4 mm) were comparable to a conventional brachytherapy seed. The NPD was composed of cross-linked 6, 8 or 10% calcium alginate, a biocompatible material (Hurtado et al. 2022). We loaded the NPD with 9.5 × 10¹³ 5 nm AuNPs, 3.5 × 10¹² 15 nm AuNPs, 4.4 × 10¹¹ 30 nm AuNPs or 9.5 × 10¹⁰ 50 nm AuNPs. The NPD inserted into a tumour may be visualized by ultrasound imaging or by SPECT/CT when the incorporated AuNPs are labeled with ¹¹¹In Fig. 7b. The NPD was porous which permitted release of smaller sized AuNPs into a tumour to aid in homogenizing the dose distribution. The amount of AuNP release in a tissue-equivalent phantom was dependent on AuNP size with 100%, 98%, 7% or 3.3% released over a 3 d period for 5, 15, 30 or 50 nm AuNPs, respectively. Release was not dependent on the percentage of calcium alginate used to construct the NPD. Release of small (5 nm) AuNPs from the NPD inserted into a s.c. MDA-MB-231 human BC tumour in a SCID mouse was visualized ex vivo by silver enhanced staining (Fig. 7c).

We subsequently studied a NPD incorporating 3.5 MBq of PEG_2K-pGlu(DOTA-[⁹⁰Y]Y)₈-LA₄-AuNPs; (1 × 10¹⁴ AuNPs; 12 nm) inserted i.t. in a s.c. 4T1 murine mammary carcinoma tumour in immunocompetent Balb/c mice that had two 4T1 tumours (Cai et al. 2022) (Fig. 8a). One of these tumours (primary tumour) was treated with a radiation nanomedicine-containing NPD while the other (secondary tumour) remained untreated. The secondary tumour was located outside the maximum 12 mm range of the β-particles emitted by ⁹⁰Y, thus was not irradiated by the radiation nanomedicine deposited in the primary tumour. In this study, we were interested to investigate if treatment of the primary tumour with the NPD incorporating PEG_2K-pGlu(DOTA-[⁹⁰Y]Y)₈-LA₄-AuNPs would cause an immune-mediated abscopal effect on the distant tumour, particularly with co-administration of anti-Programmed Cell Death Ligand-1 (anti-PD-L1) checkpoint antibodies. The abscopal (“out-of-scope”) effect was first described by Mole in 1953 who observed that X-irradiation of one tumour in a mouse with two tumours inhibited the growth of the second tumour (Mole 1953). The mechanism is believed to be due to release of damage-associated molecular patterns (DAMPs) by killed tumour cells that stimulate the immune system resulting in a cytotoxic T-cell response that inhibits the growth of the non-irradiated second tumour (Hu et al. 2017). There have been some reports of an abscopal effect in cancer patients treated with radiation, but it is rare due to immune checkpoints that block cytotoxic T-cell responses (Abuodeh et al. 2016). However, the introduction of checkpoint immunotherapy may increase the likelihood of an abscopal effect (Reynders et al. 2015) and there is a growing interest in combining radiation with immune checkpoint blockade (Nguyen et al. 2021). Imaging (Fig. 8b) and biodistribution studies after insertion of the NPD demonstrated that ⁹⁰Y activity was retained in the primary (treated) tumour with > 100–400 fold more ⁹⁰Y in this tumour than in normal tissues [400–800% injected dose/g (%ID/g) vs. < 0.5% ID/g] except for the kidneys (< 5% ID/g). The uptake of ⁹⁰Y in the distant tumour was very low (< 0.2% ID/g). Consequently, the radiation absorbed dose in the primary tumour was very high (472 Gy), while the dose in the secondary tumour was very low (0.13 Gy). Normal organ doses (0.04–0.8 Gy) were also low, except for the kidneys (4 Gy). Radiation nanomedicine treatment of the primary tumour arrested the growth of this tumour, but in addition, inhibited the growth of the distant secondary tumour by an abscopal effect (Fig. 8c). This effect was enhanced by administering anti-mouse PD-L1 antibodies. However, anti-PD-L1 antibodies alone or a NPD incorporating non-radioactive AuNPs only slightly inhibited tumour growth. There was no normal tissue toxicity. Body weight was unchanged indicating no general toxicity and there was no increase in blood alanine aminotransferase (ALT) or creatinine (Cr) indicating no liver or kidney toxicity, respectively. Blood cell counts were normal, except for white blood cells (WBCs) which were decreased. However, 4T1 tumours secrete cytokines (e.g. G-CSF) that increase WBC counts (DuPre and Hunter 2007). Healthy non-tumour bearing Balb/c mice had much lower WBC counts than tumour-bearing mice. Thus, we interpreted the decreased WBC counts in mice treated with the radiation nanomedicine vs. untreated tumour-bearing mice as response to treatment (i.e. lower tumour burden) rather than hematopoietic toxicity. These results are very encouraging for combining i.t. delivered radiation nanomedicines with checkpoint immunotherapy since they raise the intriguing idea that this approach may extend radiation nanomedicines from a local treatment to one that is both a local and a systemic treatment by harnessing a cytotoxic T-cell immune response.

We next modeled the dose distribution rate from a NPD inserted into a s.c. MDA-MB-231 human BC tumour in SCID mice containing 3.5 × 10¹⁵ AuNPs (30 nm) complexed to the β-particle emitters, ¹⁷⁷Lu or ⁹⁰Y or the AE-emitter, ¹¹¹In (Lai et al. 2017). SPECT/CT images from 1 to 168 h of a single NPD incorporating PEG_2K-pGlu(DOTA-[¹⁷⁷Lu]Lu)₈-LA₄-AuNPs inserted into a tumour in a SCID mouse were used to measure the temporal distribution of activity, plot dose maps and derive cumulative dose-volume histograms (DVH) for ¹⁷⁷Lu, ⁹⁰Y or ¹¹¹In. These doses were simulated by Monte Carlo N-Particle software (MCNP 5, Los Alamos National Security, New Mexico) and voxel-based geometry methods. ⁹⁰Y provided the greatest tumour dose penetration and most homogenous dose distribution (max: 3600 Gy, min: 7.0 Gy) compared to ¹⁷⁷Lu (max: 11,000 Gy, min: 0.06 Gy) and ¹¹¹In (max: 14,000 Gy, min: 9.8 × 10^–4 Gy). For ⁹⁰Y, none of the tumor volume received an absorbed dose lower than 0.18 Gy, while for ¹⁷⁷Lu, 88.5% of the tumor volume fraction received a dose of lower than 0.55 Gy, and for ¹¹¹In, 90.3% of the tumor volume received a dose of lower than 0.73 Gy). Modeling of insertion of 4 NPD into a hypothetical volume (9.6 × 9.6 × 9.6 mm³) that incorporated 1.8 MBq, 2.5 MBq or 25.1 MBq of ⁹⁰Y-, ¹⁷⁷Lu- or ¹¹¹In-labeled AuNPs, respectively with each NPD separated by 4.5 mm in a square formation estimated the maximum doses as 2100 Gy, 6800 Gy and 9300 Gy, respectively. The minimum doses at the volume periphery were 21.8 Gy, 0.12 Gy, and 2.2 × 10^–3 Gy. Based on this dosimetry, it was concluded that ⁹⁰Y was optimal for assuring the highest and most homogeneous dose distribution in a tumour for a NPD incorporating AuNPs.

Landscape: radiation dosimetry of radiation nanomedicines

Modeling of the radiation absorbed doses in cancer cells in vitro or in tumours in vivo deposited by radiation nanomedicines provides insight into their potential effectiveness and informs on optimizing their design. Seniwal et al. (2021) calculated cellular S-values using EGSnrc MC code and compared these to MIRDcell for spherical cells and spherical tumours with homogeneously distributed ¹⁹⁸Au, ¹⁰³Pd or ¹⁵³Sm. Based on the reported data for mangiferin (MCF)-functionalized ¹⁹⁸AuNP (Katti et al. 2018), AuNP with a ¹⁰³Pd core (Laprise-Pelletier et al. 2017) and cetuximab-conjugated carbon nanocapsules (NCs) incorporating ¹⁵³Sm (Wang et al. 2020b), they modeled the tumour uptake and washout of the NPs injected i.t., then applied a radiobiological model to predict the surviving fraction of tumour cells and the tumour volume post-treatment. Their modeling agreed with experimentally reported results for [¹⁰³Pd]Pd-AuNP and [¹⁵³Sm]Sm-cetuximab carbon NCs but not for [¹⁹⁸Au]Au-MCF-AuNPs. Finally, they predicted the therapeutic effectiveness under three different scenarios: (i) 0.3 cm³ tumour treated i.t. with 20, 40 or 60 MBq of each of the NPs, (ii) 0.3, 0.6 or 1.0 cm³ tumour treated i.t. with the same absorbed dose of each of the NPs, and (iii) 0.3 cm³ tumour exhibiting various radiosensitivities treated i.t. with the NPs. It was concluded that ¹⁹⁸Au deposited the highest dose per activity, followed by ¹⁵³Sm and ¹⁰³Pd and for large tumors, ¹⁹⁸Au and ¹⁵³Sm were more effective than ¹⁰³Pd. This study illustrated that radiobiological models are useful to guide the selection of radionuclides for constructing radiation nanomedicines and selecting the administered activity based on tumour volume, growth rate and radiosensitivity as well as NP tumour uptake and washout rate. Hyrcushko et al. (2011) modeled the absorbed dose in s.c. SCC-4 human HNSCC tumours in nude rats after i.t. infusion of [¹⁸⁶Re]Re-BMEDA-PEG-liposomes. SPECT/CT images of the tumour were acquired at 0, 2, 4, 20, 44 and 140 h p.i. and were segmented with imaging software (https://mangoviewer.com/) then imported into Matlab software (Mathworks) with voxel sizes of 0.35 × 0.35 × 0.35 mm³ for calculation of the time-integrated activity in each voxel. The absorbed dose in each tumor voxel was calculated using the dose-point kernel (DPK) convolution technique, which convolved a matrix of ¹⁸⁶Re S-values generated with EGSnrc MC simulation code with a matrix of time-integrated activities from SPECT/CT. The effective uniform dose (EUD) defined as the uniform value of biologically effective dose (BED) was calculated for each tumour based on the linear-quadratic model, voxel BED, repopulation and repair time constants. Dose-volume histograms (DVHs) were calculated from the voxel absorbed doses and demonstrated large heterogeneity of intratumoral doses (0–2000 Gy). The correlation between the average tumour absorbed dose (392–982 Gy) and tumour response was poor (R² = 0.22) but the correlation between EUD (6.10–26.99 Gy) and tumour response was excellent (R² = 0.84). This study showed that an EUD model incorporating dose heterogeneity in a tumour would be helpful in predicting responses from radiation nanomedicines. Medina et al. (2007) described a method to visually and digitally show the spatial dose distribution in a tumour following i.t. injection of [¹⁸⁶Re]Re-BMEDA-liposomes (122 nm) in rats with s.c. SCC-4 human head and neck squamous cell carcinoma tumours. Static planar γ-camera images were obtained immediately after injection and at 3 h p.i. These showed high uptake in the tumour (45–50% ID/g) but heterogeneous intratumoural distribution. The rats were sacrificed, the tumours excised and sectioned into 3 mm thick slices and these were then exposed to HS Gafchromic film at 4 °C for 18 h. The optical density of the Gafchromic film was correlated with the absorbed dose and calibrated by exposing the films to known dose rates from a ⁶⁰Co source. Dose maps for each tumour section were obtained by scanning the exposed films and the DVH calculated for each tumour.

Emfietzoglou et al. (2001) compared the dosimetry of the β-particle emitters, ⁶⁷Cu, ¹⁸⁸Re, ⁹⁰Y or ¹³¹I incorporated into liposomes and injected i.v. into mice with intramuscular Ehrlich ascites tumours or intrahepatic C26 colon cancer tumours. These radionuclides were selected to include a range of physical half-lives (0.71–8.0 d) and mean β-particle energies (0.141–0.935 MeV). Different forms of liposomes were considered based on the published biodistribution data: (i) small unilamellar vesicles (SUV; < 100 nm); (ii) multi-lamellar vesicles (MLV; > 1000 nm); (iii) SUV coated with monosialoganglioside (G_MI); and iv) SUV coated with PEG. The biodistribution in mice (%ID/organ) was scaled to a human using the ratio of human organ weight/human body weight vs. mouse organ weight/mouse body weight. It was assumed that the tumour in a human was ~ 280 g (spherical 8 cm diameter lesion). Red marrow activity was derived from blood data assuming that the ratio of liposomes concentration in red marrow versus the blood was 0.36 (Sgouros 1993). The MIRD schema was used to calculate the average doses in the human for the tumour, liver, spleen, kidneys, lungs, red marrow and total body. The dosimetry projected that SUV incorporating ⁹⁰Y were optimal, since administration of 13.4 GBq to a human would deliver an effective tumour dose (20 Gy) and tolerable doses in the liver (25 Gy) and red marrow (1.4 Gy). However, these doses in the liver and red marrow approach the maximum tolerated doses of radiation for these tissues (30–32 Gy for liver and 2–5 Gy for red marrow) (Wahl et al. 2021), again indicating the challenge of delivering effective tumour doses while avoiding toxicity on normal tissues for i.v. injected radiation nanomedicines. This same group (Emfietzoglou et al. 2005) estimated the dosimetry of the β-particle emitters, ³²P, ⁹⁰Y, ¹⁸⁸Re, ⁶⁷Cu or ¹³¹I or AE-emitters, ¹²³I or ¹²⁵I incorporated into SUV (50–100 nm) or MLV (80–1000 nm) liposomes modified with anti-PSMA J591 antibodies and incubated in vitro with LNCaP human prostate cancer spheroids (200 μm diameter). Regardless of the liposomal form, high energy β-emitters (e.g. ⁹⁰Y) provided more homogeneous absorbed doses in the spheroids vs. low energy AE-emitters (e.g. ¹²³I). These results agree with our reported dosimetry modeling of tumours implanted i.t. with a NPD incorporating AuNPs complexed to the β-particle emitters, ¹⁷⁷Lu or ⁹⁰Y or the AE-emitter, ¹¹¹In, where the higher energy β-particles emitted by ⁹⁰Y provided the most homogeneous dose distribution (Lai et al. 2017).

Nanoscopic and microscopic dose deposition

As discussed earlier, interaction of X-rays with AuNPs causes release of secondary AE and PE that enhance the RBE of XRT for killing cancer cells, i.e. dose-enhancement effect. Emission of α-particles, β-particles or AE by radionuclides may also interact with dense inorganic NPs to produce secondary AE and PE that enhance dose deposition and increase the RBE on the nanoscopic or microscopic scale. Gholami et al. (2019) reported a dose simulation study which examined the interaction of α-particles emitted by ²¹³Bi or ²²³Ra or β-particles emitted by ⁶⁷Cu, ¹⁷⁷Lu or ⁹⁰Y with spherical Fe₂O₃ nanoparticles (IONPs). These radionuclides were distributed in a 1 nm wide shell surrounding the 6 nm core of the IONPs. A cluster of 500 IONPs was distributed in the center of a water phantom cube (3.5 × 3.5 × 3.5 μm³) and the separation distance between IONPs varied from 1 to 50 nm. The study showed that at a separation distance of 1 nm, there was 20.7%, 19.3%, 18.3%, 17.6% and 16.7% increased dose for IONPs bound to ²²³Ra, ²¹³Bi, ⁹⁰Y and ⁶⁷Cu vs. radionuclides without IONPs, respectively. The dose-enhancement effect decreased as separation distance increased. Dose-enhancement was due to the release of secondary electrons from the IONPs following interaction with the α- or β-particles emitted by the radionuclides. Maschmeyer et al. (2020) conduced a MC dose-modeling study to estimate the nano-Radio Enhancement Ratio (nano-RER) defined as the ratio of the number of secondary electrons produced with/without 5 nm superparamagnetic iron oxide NPs (SPIONs) bound to ⁶⁷Cu. The nano-RER for a single [⁶⁷Cu]Cu-SPION decreased dramatically as the distance from the SPION increased. The highest nano-RER was 1.15 (i.e. 15% increase in secondary electrons) which occurred within 100 nm of the SPION surface. Clustering of the SPIONs and larger SPION clusters increased the nano-RER, but the nano-RER was decreased as the separation distance between the clusters increased.

The effect of the AE emissions from ¹²⁵I, ¹¹¹In or ^99mTc encapsulated in nanoshells or coated on spherical NPs composed of Fe, Ag, Gd, Au or Pt was modeled by Sung et al. (2016). Doses were estimated for a water phantom using MC simulation with Geant4-Penelope code. The inner/outer diameters of the nanoshells or the diameter of nanospheres were varied to determine the effect of NP size on dose-enhancement vs. radial distance from the NP surface. The nanoshells encapsulating these radionuclides stopped low energy electrons and decreased the number of electrons emitted at the NP-water interface. Thus, the total dose per decay at the same radial distance was highest for a nanosphere, followed by no NP, then by a nanoshell. For nanoshells encapsulating these radionuclides, the dose-enhancement was < 1 at a radial distance < 10 nm but peaked at ~ 20 nm for most studied combinations. In contrast, for nanopsheres coated with these radionuclides the dose-enhancement was highest at the NP-water interface, then decreased dramatically within 5 nm from the surface of the NP. The local microscopic doses at radial > 100 nm for NP were not larger than without NP. This study concluded that AE therapy combined with NP could potentially provide better therapeutic effect than AE alone, however, the choice of AE emitters and the design of NP should be optimized based on the distance between AE emitters and biological targets. Hahn et al. (2021) estimated the absorbed dose in various subcellular compartments (cell membrane, cytoplasm, nucleus and mitochondria) of Chinese hamster ovary (CHO) cells by ¹⁹⁸AuNPs located either randomly in cytosol or in cell nucleus by MC methods using Geant4 code combined with the Topas and TsSphericalCellSphericalNP model and two AuNP distribution models, simplified continuous Au or discrete AuNP (5 nm)-geometric distribution. The purpose of the study was to compare the effect of AuNP distribution models on the calculated dose enhancement by AuNP and to understand the factors such as locations of AuNPs and the % mass of Au in the cell influencing the dose enhancement of AuNP. The continuous model underestimated the energy deposition per decay of ¹⁹⁸Au in most compartments in the cells by 4–15% except cell membrane. For both models, the energy deposited per decay in cell organelles increased as the mass Au % increased. Increasing the number of AuNPs targeted to the nucleus increased the energy deposited in the whole cell and the radiosensitive nucleus, but decreased the energy deposited in the cytoplasm, mitochondria and cell membrane compared to AuNPs randomly distributed in the cytoplasm. This study helped to guide the design of targeted ¹⁹⁸AuNP for more effective cancer therapy.

Journey: ¹⁷⁷Lu-Labeled NPs for treatment of GBM

A promising application of locally-administered radiation nanomedicines is treatment of glioblastoma multiforme (GBM) since metastasis of GBM outside the brain is very rare. GBM is the most common and most lethal form of brain cancer. GBM is currently treated by surgery, external radiation and temozolomide chemotherapy (Stupp et al. 2005). However, almost all patients develop recurrence, often within 2 cm of the surgical margins. Recurrent GBM is very difficult to treat and consequently, the median survival of patients with GBM is < 18 months (Delgado-Lopez and Corrales-Garcia 2016). Local infusion of radiation nanomedicines by convection enhanced delivery (CED) into the surgical cavity post-resection may eradicate residual tumour at the margins and prevent recurrence, potentially improving survival. We studied a radiation nanomedicine for treatment of GBM by stereotaxically infusing 1.1 MBq [¹⁷⁷Lu]Lu-MCP-AuNPs (~ 23 nm; 4 × 10¹¹ AuNPs) by CED into small (~ 2 mm) luciferase-transfected U251-Luc human GBM tumours in the brain in NRG mice (Georgiou et al. 2023) (Fig. 9a). SPECT/CT imaging up to 21 d p.i. showed retention of activity at the i.t. infusion site with minimal redistribution to other regions of the brain or to organs outside the brain (Fig. 9b). Biodistribution studies revealed that activity in the tumour-involved hemisphere was 200–300% ID/g, while activity in the normal brain was only 1–2% ID/g and in other organs including the liver and spleen was < 3% ID/g. The retention of [¹⁷⁷Lu]Lu-MCP-AuNPs in the brain is believed to be due to an “anchoring” effect of the AuNPs, due to the bidirectional nature of the blood–brain barrier (D'Amico et al. 2021) the large AuNP construct was unable to cross into systemic circulation, while [¹⁷⁷Lu]Lu-MCP not bound to AuNPs was rapidly eliminated from the brain within 72 h post-infusion. The radiation absorbed dose in the tumour was 600 Gy while the doses to the surrounding brain were 100-fold lower (6.4 Gy) and to the contralateral hemisphere of the brain were 2000-fold lower (0.3 Gy). Doses to organs outside the brain were < 0.2 Gy, including in the liver and spleen. Treatment of NRG mice U251-Luc tumours with [¹⁷⁷Lu]Lu-MCP-AuNPs achieved almost complete tumour growth arrest demonstrated by bioluminescence imaging (BLI) (Fig. 9c) or MRI (Fig. 9d) while tumours in control mice treated with unlabeled AuNPs or normal saline grew rapidly. No visible tumour was found at 28 d p.i. of [¹⁷⁷Lu]Lu-MCP-AuNPs with the treatment evaluated by MRI and by ex vivo histological staining. All normal saline treated mice died within 39 d and mice treated with unlabeled AuNPs died within 45 d, but 5/8 mice treated with [¹⁷⁷Lu]Lu-MCP-AuNPs survived up to 150 d. There was no apparent normal tissue toxicity including to the brain. These results are very promising for CED of radiation nanomedicines for treatment of GBM.

Landscape: radiation nanomedicines for GBM

No other studies of radiolabeled AuNPs for treatment of GBM have been reported, but liposomal NPs labeled with the β-particle emitters, ¹⁸⁶Re or ¹⁸⁸Re have been investigated. Cikankowitz et al. (2017) studied [¹⁸⁸Re]Re-nanocapsules (NCs) administered by CED for treatment of orthotopic human Lab1 GBM tumours in nude NMRI mice. Activity was retained (> 70%) in the tumour and peritumoural space with no redistribution to the contralateral brain hemisphere. Treatment of mice with Lab1 tumours with two amounts (3 MBq each) of [¹⁸⁸Re]Re-NCs separated by 7 d increased median survival to 56 d versus 20–21 d for mice receiving unlabeled NCs or no treatment. Moreover, radiation nanomedicine treatment decreased tumour volume by > 50% at 18 d post-CED compared to mice treated with unlabeled NCs. There was no toxicity observed on the normal brain. This same group (Vanpouille-Box et al. 2011) studied [¹⁸⁸Re]Re-NCs (two amounts of 2.8 MBq separated by 6 d) administered by CED for treatment of 9L rat glioma tumours in rats achieving cure rates of > 80%, which may have been due to a combined radiation and immune response, since immune cells were found infiltrating the tumour. Median survival was increased to > 120 d in rats treated with [¹⁸⁸Re]Re-NCs versus < 30 d in untreated rats. The greater effectiveness of CED for radiation nanomedicines to treat GBM is illustrated through a study by Huang et al. (2015) who treated Fisher rats with orthotopic F98 glioma tumours with i.v. injected [¹⁸⁸Re]Re-liposomes at much higher amounts (333 MBq). Tumour uptake was only 2% ID/g and median survival was only slightly increased to 20 d versus 18 d for untreated rats. Body weight decreased indicating normal tissue toxicity. Séhédic et al. constructed [¹⁸⁸Re]Re-loaded lipid nanocapsules (LNCs) modified with 12G5 antibodies to target C-X-C chemokine receptor type 4 (CXCR4), a receptor involved in GBM tumour growth and invasiveness mediated by matrix metalloproteinases (MMPs) (Zhang et al. 2005). Treatment of SCID mice with orthotopic U87MG CXCR4-positive human GBM tumours with 2.7 MBq of [¹⁸⁸Re]Re-12G5-LNCs increased median survival to 74 d versus 38 d for untreated mice or 34 d for mice treated with unlabeled and non-targeted LNCs. Non-targeted [¹⁸⁸Re]Re-LNCs were also effective for treating these GBM tumours. Philips et al. (Phillips et al. 2012) examined the effect of infusion volume of [¹⁸⁶Re]Re-liposomes administered by CED in rats with orthotopic luciferase-transfected U-87 MG-luc2 human GBM tumours. Large infusion volumes (100 μL) were associated with redistribution to the brainstem and cerebellum, while small volumes (25 μL) were retained in the tumour for up to 96 h. Absorbed doses as high as 1800 Gy were deposited in GBM tumours by CED of up to 4.6 MBq of [¹⁸⁶Re]Re-liposomes. There was a major treatment response with almost complete elimination of tumour detected by BLI or MRI. Median survival was increased to 126 d for rats treated with the radiation nanomedicine versus 49 d for untreated rats. There was no apparent normal tissue toxicity. Single administration of [¹⁸⁶Re]Re-liposomes by CED was evaluated in a Phase I/IIA dose escalation trial in patients with recurrent GBM which found that injected activities up to 1535 MBq (41.5 mCi) were safe and without dose-limiting toxicities (Brenner et al. 2023).

Schultz et al. constructed metallofullerenes labeled with ¹⁷⁷Lu (Shultz et al. 2011). CED of ¹⁷⁷Lu-labeled metallofullerenes (0.25–1.35 MBq) into orthotopic U87MG tumors in nude mice improved median survival with > 80% of mice treated with 1.35 MBq surviving > 100 d, while untreated mice survived < 29 d. Moreover, tumours in treated mice were smaller assessed by ex vivo histological staining (Wilson et al. 2012). Together, the results of these studies confirm our findings (Georgiou et al. 2023) that radiation nanomedicines administered by CED deposit high absorbed doses in GBM tumours in animal models that result in strong tumour growth-inhibitory effects, but are not toxic to normal tissues including normal brain, due to the restricted diffusion within the brain or redistribution to organs outside the brain mediated by the anchoring effects of NPs.

Landscape: NPs labeled with α-particle emitting radionuclides

Radionuclides that emit α-particles are very attractive for incorporation into NPs because several MeV of energy is released during α-decay. This energy is deposited over a short range (50–100 μm) resulting in high LET (50–230 keV/μm) that is extremely potent for killing cancer cells (Aghevlian et al. 2017). In contrast, β-particles deposit their energy over several mm range in tissues, resulting in low LET (< 0.1 keV/μm) which is less effective for damaging DNA in cancer cells. Moreover, α-particles may directly inflict lethal DNA DSBs while β-particles rely on indirect DNA damage mediated by reactive oxygen species (ROS). Thus, α-particles may be more effective than β-particles for treating hypoxic tumours (Aghevlian et al. 2017).

Actinium-225

²²⁵Ac (t_1/2 = 10 d) is an α-particle emitting radionuclide that decays through a series of daughter products that are themselves α-particle or β-particle emitters to stable ²⁰⁹Pb. Most studies of radiation nanomedicines incorporating α-particle emitters have used liposomes. Chang et al. (2008) actively loaded ²²⁵Ac into PEGylated liposomes (~ 121 nm) by complexing ²²⁵Ac with the ionophores, oxine or A23187 at 65 °C and then mixing these complexes with liposomes. Loading efficiency for ²²⁵Ac was high (up to 60–80%) but there was rapid and extensive release of ²²⁵Ac (50–80%) in vitro within 2 h at 37 °C in PBS or medium containing serum. This instability would make these liposomal formulations not feasible for therapy studies. Bandekar et al. (2014) incorporated ²²⁵Ac into PEGylated liposomes (~ 107 nm) modified with anti-PSMA J591 antibodies or A10 aptamer. These liposomes incorporated DOTA to strongly complex ²²⁵Ac. Loading was achieved at 65–67 °C by incubating liposomes with ²²⁵Ac complexed to A23187 ionophore with transchelation of ²²⁵Ac within the liposome to DOTA. Loading efficiency ranged from 58 to 85%. These liposomes were relatively stable, retaining ~ 70% of ²²⁵Ac in vitro up to 24 h when incubated at 37 °C in medium containing serum. J581-modified liposomes exhibited greater binding to PSMA-positive LnCAP human and Mat-Lu rat prostate cancer than A10-modified liposomes. There was no binding to PSMA-negative cell lines. [²²⁵Ac]Ac-DOTA-J591-liposomes were more cytotoxic than [²²⁵Ac]Ac-A10-liposomes in vitro against LNCap and Mat-Lu cells, decreasing cell viability to 10–20% after incubation for 24 h at up to 0.4 MBq/mL. Non-targeted [²²⁵Ac]Ac-DOTA-liposomes were also cytotoxic on PSMA-positive cells and targeted [²²⁵Ac]Ac-DOTA-J591-liposomes and [²²⁵Ac]Ac-DOTA-A10-liposomes demonstrated cytotoxicity towards PSMA-negative cells, but these effects were lower than for targeted liposomes on PSMA-positive cells. Sofou et al. (2007) synthesized PEGylated multivesicular liposomes (MUVELs) composed of large liposomes (~ 400 nm) that contained entrapped small vesicles (~ 100 nm) to aid in retention of ²²⁵Ac daughters and limit normal tissue toxicity. ²²⁵Ac complexed to DOTA was passively loaded into the liposomes during synthesis. The efficiency of loading was low (< 10%) but ²²⁵Ac was stably retained (> 98%) over 30 d by these MUVELs. Unfortunately, there was release of the ²¹³Bi daughter of ²²⁵Ac (70%). These [²²⁵Ac]Ac-DOTA-MUVELs were further modified with trastuzumab and showed specific binding and internalization by HER2-positive SKOV3-NMP2 human ovarian cancer cells. This same group compared cationic and zwitterionic PEGylated liposomes of different sizes (~ 180, 400 or 600–650 nm) for retaining ²²⁵Ac and its daughters (Sofou et al. 2004). It was theorized that if the liposome dimension was sufficiently large, it would retain ²¹³Bi and other ²²⁵Ac daughters, particularly as these are ionic in nature and would not be able to escape by penetrating the liposomal lipid membrane. ²¹³Bi retention was greater for 600 nm versus 100 nm zwitterionic liposomes. Nonetheless, ²¹³Bi retention was very low (< 12%) for zwitterionic or cationic liposomes. ²²⁵Ac was retained better in zwitterionic liposomes (> 90%) than in cationic liposomes (75–85%).

A challenge in using NPs incorporating α-particle emitters for cancer therapy is the short range of α-particles (50–100 μm) since not all tumour cells within a lesion may be irradiated due to the limited penetration of NPs into tumours (Lee et al. 2010). Zhu et al. (2017) aimed to address this challenge by constructing pH-responsive liposomes that incorporated ²²⁵Ac complexed to DOTA that would release their payload at the slightly acidic pH of the tumour microenvironment. They treated small (200 μm) or large (400 μm) spheroids composed of HER2-positive human BC cells in vitro with trastuzumab-modified pH-responsive [²²⁵Ac]Ac-DOTA-liposomes or non-pH responsive [²²⁵Ac]Ac-DOTA-liposomes. While the liposomal carrier remained mostly at the surface of the spheroids, only pH-responsive liposomes showed uniform ²²⁵Ac activity diffusion within the spheroids, while non-pH responsive liposomes showed low activity in the centre and higher activity on the surface. DNA DSBs measured by γ-H2AX immunofluorescence were predominant near the surface for all liposomes, but there was higher γ-H2AX intensity near the centre of the spheroid for pH-responsive [²²⁵Ac]Ac-DOTA-liposomes. In addition, pH-responsive [²²⁵Ac]Ac-DOTA-liposomes were more effective than non-pH responsive liposomes for inhibiting the growth of HER2-positive BT-474 and HER2-negative MDA-MB-231 spheroids. In mice with s.c. HER2-negative MDA-MD-231 tumours, i.v. injection of 9.25 kBq of pH-responsive [²²⁵Ac]Ac-DOTA-liposomes inhibited tumour growth and prolonged survival, whereas non-pH responsive liposomes were not effective. However, the MTD of these non-targeted [²²⁵Ac]Ac-DOTA-liposomes after i.v. injection in healthy mice was 14.8 kBq, causing pneumonitis and decreased spleen size, although there was no renal or liver toxicity.

Inorganic NPs have been loaded with ²²⁵Ac to construct radiation nanomedicines. McLaughlin et al. (2014) synthesized NPs composed of ²²⁵Ac embedded in lanthanum (La) and gadolinium phosphate (GdPO₄) layers that were then coated with a gold (Au) shell. These NPs were further modified with antibodies that bind murine thrombomodulin expressed in lung endothelium. [²²⁵Ac]Ac–La–GdPO₄–Au NPs localized in the lungs of mice and retained the ²¹³Bi daughter in lung tissue, suggesting that these NPs were stable and did not release the daughter products of ²²⁵Ac. Treatment of mice with murine EMT-6 mammary carcinoma metastases in the lungs by i.v. injection of 44 kBq of [²²⁵Ac]Ac–La–GdPO₄–Au NPs reduced the number of EMT-6 lung colonies (metastases) by fourfold compared to untreated mice. Karpov et al. (2022) incorporated ²²⁵Ac into silica (SiO₂) NPs (~ 100 nm) that were then surface-coated with titanium doxide (TiO₂) or gold (Au) to aid in the retention of ²²⁵Ac and its daughters. Uncoated [²²⁵Ac]Ac–SiO₂ NPs released 70% of ²²⁵Ac by 30 d when incubated in human serum, whereas [²²⁵Ac]Ac–SiO₂–TiO₂ NPs and [²²⁵Ac]Ac–SiO₂–Au NPs released only 0.3% and 2.6%, respectively. The release of ²²¹Fr and ²¹³Bi daughters of ²²⁵Ac at 30 d was 58% and 46%, respectively for uncoated [²²⁵Ac]Ac–SiO₂ NPs, but this was reduced to 15% and 5%, respectively for coated [²²⁵Ac]Ac–SiO₂–TiO₂ NPs and to 20% and 12%, respectively for [²²⁵Ac]Ac–SiO₂–Au NPs. Administration of 74 kBq i.v. of uncoated [²²⁵Ac]Ac–SiO₂ NPs caused lung toxicity in mice, but this was not discovered for [²²⁵Ac]Ac–SiO₂–TiO₂ or [²²⁵Ac]Ac–SiO₂–Au NPs. Further, slight histological changes were found in the liver for [²²⁵Ac]Ac–SiO₂ NPs but not for [²²⁵Ac]Ac–SiO₂–TiO₂ or [²²⁵Ac]Ac–SiO₂–Au NPs. Renal toxicity is a reported concern for the released ²¹³Bi daughter of ²²⁵Ac, and severe inflammation was noted in the kidneys of mice injected with uncoated [²²⁵Ac]Ac–SiO₂ NPs but this was not observed for [²²⁵Ac]Ac–SiO₂–TiO₂ or [²²⁵Ac]Ac–SiO₂–Au NPs. These results suggest that coating [²²⁵Ac]Ac–SiO₂ NPs with TiO₂ or Au shells retains ²²⁵Ac and its daughters within the NPs, reducing normal tissue toxicity.

Single walled carbon nanotubes (SWCNTs) are nanometer-sized cylindrical structures composed of fullerene graphine (Ajayan 1999). Matson et al. (2015) loaded ²²⁵Ac³⁺ with/without co-loading of gadolinium (Gd³⁺) ions into 20–80 nm long SWCNTs. Loading efficiency for ²²⁵Ac³⁺ was very high (> 95%) while co-loading of ²²⁵Ac³⁺ and Gd³⁺ was only 50% due to competition with Gd³⁺ ions. However, co-loading of ²²⁵Ac³⁺ and Gd³⁺ provided greater stability to release of ²²⁵Ac when incubated for 2 h at 37 °C in serum (80% vs. 40%), which was hypothesized to be due to formation of Ac-Gd clusters within the side-wall defects in the SWCNTs. No cytotoxicity studies in vitro or tumour therapy studies in vivo were conducted. Mulvey et al. (2013) constructed 350 nm length SWCNTs (diameter ~ 1.2 nm) conjugated to DOTA complexed to ²²⁵Ac or ¹¹¹In that were also modified with complementary morpholino oligonucleotides (cMORF) for pre-targeted delivery to tumours that bound MORF-conjugated anti-CD20 rituximab. To assess the toxicity of the [²²⁵Ac]Ac-DOTA-cMORF-SWCNTs, increasing amounts (16.6–100 kBq) were administered i.v. to healthy Balb/c mice. Dose-dependent bone marrow toxicity was found for mice injected with 50–100 kBq and amounts > 83 kBq caused death. Thus, treatment studies were performed in SCID mice with CD20-positive intraperitoneal (i.p.) Daudi B-cell lymphoma tumours. The mice were administered rituximab-MORF, followed 24 h later with 12.3–36.9 kBq of [²²⁵Ac]Ac-DOTA-cMORF-SWCNTs. BLI demonstrated complete eradication of Daudi tumours in mice receiving 24.6 or 36.9 kBq of [²²⁵Ac]Ac-DOTA-cMORF-SWCNTs, while control mice injected with normal saline or unlabeled DOTA-cMORF-SWCNTs exhibited rapid tumour growth. Mice pre-targeted with an irrelevant anti-CD33-MORF followed by [²²⁵Ac]Ac-DOTA-cMORF-SWCNTs exhibited a transient tumour response but subsequently rapidly progressed. Ruggiero et al. (2010) synthesized 200–1000 nm length SWCNTs (diameter 1.4 nm) modified with DOTA to complex ²²⁵Ac or with desferrioxamine (DFO) for labeling with ⁸⁹Zr. These SWCNTs were further modified with E4G10 antibodies to target the tumour neovasculature. Athymic mice with s.c. LS174T human colon cancer xenografts were treated with 16.1 kBq of [²²⁵Ac]Ac-DOTA-E4G10-SWCNTs by i.v. injection. PET was performed in mice with s.c. LS174T tumours injected i.v. with 4.2 MBq of [⁸⁹Zr]Zr-DFO-E4G10-SWCNTs. PET showed high liver and kidney uptake and low tumour uptake (~ 0.5% ID/g at 24 h p.i.). Nonetheless, high specific activity (851 GBq/g) of [²²⁵Ac]Ac-DOTA-E4G10-SWCNTs transiently inhibited tumour growth and prolonged survival compared to mice treated with irrelevant anti-KLH-modified SWCNTs or no treatment. Normal tissue toxicity was not evaluated. Despite some promising results for ²²⁵Ac-labeled SWCNTs as radiation nanomedicines, it should be recognized that unmodified CNTs have been found to be cytotoxic against many normal cell types, due to their water-insolubility which limits their elimination (Reilly 2007). Functionalization of SWCNTs to increase their water-solubility greatly reduces their cytotoxicity and promotes blood clearance.

Other α-particle emitters

²¹³Bi (t_1/2 = 46 min) is a daughter radionuclide of ²²⁵Ac that decays by β-particle emission (98%; E_βmax = 0.444 MeV) to ²¹³Po (t_1/2 = 4.2 µs) which then decays by α-particle emission (E_α = 8.4 MeV) to ²⁰⁹Pb (t_1/2 = 3.25 h). ²⁰⁹Pb decays by β-particle emission (E_βmax = 0.198 MeV) to stable ²⁰⁹Bi. Alternatively, ²¹³Bi decays by α-particle emission (2%; E_α = 5.5–5.9 MeV) to ²⁰⁹Tl (t_1/2 = 2.2 min) which decays to ²⁰⁹Pb by β-particle emission (E_βmax = 0.659 MeV) to stable ²⁰⁹Bi. Lingappa et al. (2010) incorporated ²¹³Bi complexed to CHX-A′′-DTPA into PEGylated liposomes (100 nm) that were modified with HER2/neu antibodies. [²¹³Bi]Bi-CHX-A′′-DTPA-anti-HER2-liposomes were more cytotoxic than [²¹³Bi]Bi-CHX-A′′-DTPA-liposomes in vitro against HER2/neu–expressing NT2.5 murine mammary carcinoma cells. Biodistribution studies in neu-N transgenic mice with metastatic NT2.5 tumours at 4 h post i.v. injection of [²¹³Bi]Bi-CHX-A′′-DTPA-anti-HER2-liposomes revealed high uptake in the spleen (40% ID/g) but relatively low uptake (< 5% ID/g) in other tissues. Tumour uptake was maximal at 0.5 h p.i. (3% ID/g) but decreased at later time points. Hematopoetic toxicity was the major dose-limiting toxicity for [²¹³Bi]Bi-CHX-A′′-DTPA-anti-HER2-liposomes. Treatment of mice with metastatic NT2.5 tumours with 19.2 MBq of [²¹³Bi]Bi-CHX-A′′-DTPA-anti-HER2-liposomes improved the median survival to 38 d versus 29 d for untreated mice and 27 d for mice treated with unlabeled liposomes. ²¹²Pb (t_1/2 = 10.6 h) decays by β-particle emission (E_βmax = 0.57 MeV) to ²¹²Bi (t_1/2 = 60.6 min) which then decays to ²¹²Po (t1/2 = 0.3 μs) by β-particle emission (64%; E_βmax = 2.2 MeV). ²¹²Po then decays by α-particle emission (E_α = 8.8 MeV) to stable ²⁰⁸Pb. Alternatively, ²¹²Bi decays by α-particle emission (36%; E_α = 6.1 MeV) to ²⁰⁸Tl (t_1/2 = 3.0 min) which decays to stable ²⁰⁸Pb by β-particle emission (E_βmax = 1.8 MeV). Thus, ²¹²Pb is an attractive radionuclide for incorporation into NPs due to its multiple α- and β-particle emissions. Pikul et al. (1987) incorporated ²¹²Pb complexed to dextran into large unilamellar liposomes (350–500 nm). Treatment of B16F10 murine melanoma cells in vitro with [²¹²Pb]Pb-dextran-liposomes decreased their survival by 85% with as few as 5–7 α-particles traversing the cells. ²¹¹At (t_1/2 = 7 h) decays through ²¹¹Po and ²⁰⁷Bi daughter products to stable ²⁰⁷Pb, emitting α-particles (Eα = 5.9–7.4 MeV). Kato et al. (2021) constructed PEGylated [²¹¹At]At-labeled AuNPs and injected these i.t. in rats with s.c. C6 glioma or mice with s.c. PANC-1 human pancreatic cancer xenografts. Activity was strongly retained in these tumours with no apparent redistribution to other tissues. Smaller AuNPs (30 nm) diffused more readily and homogeneously within tumours than larger (120 nm) AuNPs. Treatment of tumour-bearing rats with 1.4 MBq or mice with 1.2 MBq of [²¹¹At]At-PEG-AuNPs arrested tumour growth without causing toxicity, assessed by monitoring body weight. Mean tumour size at 40 d post-treatment was tenfold lower for rats or mice receiving [²¹¹At]At-PEG-AuNPs than in untreated mice.

²²³Ra (t_1/2 = 11.4 d) decays through several daughter radionuclides (²¹⁹Rn, ²¹⁵Po, ²¹¹Pb, ²¹¹Bi, ²¹¹Po and ²⁰⁷Tl) to stable ²⁰⁷Pb, by emitting 4 α-particles (E_α = 5.0–7.5 MeV) as well as by emission of several β-particles. ²²³RaCl₂ (Xofigo; Bayer) is approved for treatment of painful bone metastases in patients with castration-resistant prostate cancer and is the only α-particle emitting therapeutic agent in routine clinical use (McGann and Horton 2015). Since there are limited chelators available to complex radium to biomolecules (Henriksen et al. 2002), incorporating ²²³Ra into NPs that are surface-modified with tumour targeting vectors could provide a route to selective delivery of ²²³Ra to tumours. Gaweda et al. (2020) synthesized spherical ²²³Ra barium ferrite NPs ([²²³Ra]BaFeNPs) that were further modified with trastuzumab via a 3-phosphonopropionic acid (CEPA) linker to bind to HER2. Based on dynamic lght scattering (DLS) analysis, trastuzumab conjugation increased the hydrodynamic diameter of BaFeNPs in PBS from 116 to 218 nm. [²²³Ra]BaFeNPs retained > 97–98% of ²²³Ra and 88% and 94% of the ²¹¹Bi and ²¹¹Pb daughters, respectively, in human serum up to 30 days. [²²³Ra]BaFeNPs were specifically bound, internalized and localized in the nucleus of HER2-positive SK-OV-3 human ovarian cancer cells. [²²³Ra]BaFeNPs were more cytotoxic to SK-OV-3 cells and SK-OV-3 spheroids in vitro than ²²³RaCl₂ or non-targeted [²²³Ra]BaFeNPs. Zeolites are crystalline microporous aluminosilicates, that include zeolite A usually synthesized as the Na⁺ form [Na₁₂Al₁₂Si₁₂O₄₈ ≤ 27 H₂O; NaA]. Czerwinska et al. (2020) constructed NaA nanozelite NPs (120 nm) labeled with ²²³Ra by exchanging ²²³Ra with Na⁺. These NPs were further modified with silane-PEG-NH₂ to enable conjugation to N-hydroxysuccinimide (NHS)-derivatized anti-PSMA monoclonal antibodies D2B. [²²³Ra]RaA-silane-PEG-D2B NPs retained > 95% of ²²³Ra and its daughters, ²¹¹Bi and ²¹¹Pb up to 12 days in 0.9% NaCl and human serum. [²²³Ra]RaA-silane-PEG-D2B NPs were cytotoxic in vitro to DU-145 and LNCaP human prostate cancer cells. However, i.v. injection of [²²³Ra]RaA-silane-PEG-D2B NPs in LNCAP tumor-bearing nude mice, resulted in high uptake in the liver, spleen, lungs, and bone (Lankoff et al. 2021). Hematopoietic and liver toxicity were limiting factors. Thus, it was concluded that i.v. administration of [²²³Ra]RaA-silane-PEG-D2B NPs was not feasible. However, local administration of [²²³Ra]RaA-silane-PEG-D2B NPs may overcome these limitations, but was not studied.

Landscape: future clinical translation of radiation nanomedicines

Several nanomedicines for delivery of chemotherapeutic drugs have completed clinical trials and were approved for treatment of cancer (Thapa and Kim 2023). However, to date no radiation nanomedicine has been approved for cancer treatment. Nonetheless, ^99mTc-sulfur colloid is a radiolabeled NP (particle size ~ 300 nm) that is injected i.v. and has been used routinely for decades in nuclear medicine for imaging the liver, spleen and bone marrow (Geslien et al. 1976). More recently, filtered ^99mTc sulfur colloid with a smaller particle size (~ 100 nm) injected interstitially has been used to detect the sentinel lymph node in patients with breast cancer (Giammarile et al. 2013). Some other radiolabeled NPs have been studied clinically for tumour imaging. Lee et al. (2017) investigated PET imaging with a ⁶⁴Cu-labeled liposomal drug delivery system (MM-302) to probe the EPR properties of tumours in patients with metastatic breast cancer, which may predict response to these NPs incorporating chemotherapeutic drugs. Nonetheless, these are examples of radiolabeled NPs for imaging purposes and not for radiotherapeutic applications. The challenge to advancing radiation nanomedicines for cancer treatment is sequestration by the liver and spleen and low tumour uptake after i.v. injection which results in a low therapeutic index as revealed in many preclinical studies discussed in this article,. However, as pointed out, loco-regional administration of radiation nanomedicines is a promising route that overcomes these limitations. Interestingly, a first-in-human clinical trial of ¹⁸⁸Re-labeled nanoliposomes for local treatment of GBM administered by CED has been launched (ClinicalTrials.gov identifier: NCT01906385). SPECT imaging of patients in this trial demonstrated retention of ¹⁸⁸Re-labeled nanoliposomes at the infusion site in the brain with no redistribution to other regions of the brain (Fig. 10) (Woodall et al. 2021) These imaging results in patients with GBM administered ¹⁸⁸Re-labeled nanoliposomes by CED are very similar to those that we reported for [¹⁷⁷Lu]Lu-MCP-AuNPs infused by CED in NRG mice with orthotopic human GBM tumours (Fig. 9b) (Georgiou et al. 2023).

Regulatory guidelines for nanomedicines

To our knowledge, there are no specific regulatory guidelines for radiation nanomedicines. However, guidelines for nanomedicines have been published by the U.S. FDA (Paradise 2019; Thapa and Kim 2023) and the European Medicines Agency (EMA) and Health Canada (Dri et al. 2023). The quality requirements for nanomedicines vary between regulatory agencies, but generally include evaluation of the physico-chemical properties of the NPs such as particle size and morphology, stability, surface charge, drug loading and release, sterility and endotoxins testing and toxicity assessment (Anonymous 2022; Dri et al. 2023). Radiation nanomedicines would require additional tests for measurement of radiochemical purity (RCP) and radionuclide purity (RNP), stability against loss of radiometal in serum, organ dosimetry and radiation toxicity. Good Manufacturing Practices (GMP) for radiation nanomedicines remain to be established and are beyond the scope of this article. Nonetheless, Hernandez-Jimenez et al. (2022) reported production of ¹⁷⁷Lu[Lu]-iFAP/iPSMA NPs (23 nm) under GMP conditions in an ISO Class 5 clean air environment. Quality control testing included measurement of RCP and RNP, particle size, surface functionalization, heavy metal content, carrier lutetium quantification, and sterility and endotoxins tests. Finally, there is the possibility that radiation nanomedicines packaged and retained in an implantable delivery system, e.g. a NPD incorporating radiolabeled AuNPs as previously reported by our group (Cai et al. 2022), may be considered brachytherapy and regulated as a medical device (Beers et al. 2019).

Conclusions

Radiation nanomedicines have shown great promise for treating cancer in preclinical animal tumour models. Local intratumoural administration avoids sequestration of NPs by the liver and spleen, depositing high absorbed doses in tumours and low doses in normal organs. This provides high effectiveness for treating tumours, while minimizing normal tissue toxicity. Opportunities to locoregionally deliver radiation nanomedicines to cancers, particularly for tumours that are anatomically restricted should be explored, based on the highly encouraging results obtained to date for local cancer treatment in preclinical animal tumour models. Future research opportunities in the field of radiation nanomedicines include optimizing the design of NPs to minimize liver and spleen uptake after i.v. injection, development of new radiochemistry to incorporate therapeutic radionuclides into NPs, strategies to actively transport NPs to tumours by conjugating targeting ligands, and studies of radiation nanomedicines combined with checkpoint immunotherapy to promote an immune-mediated cytotoxic T-cell response to amplify and extend their therapeutic effects.

Availability of data and materials

Not applicable.

Abbreviations

5-FU:: 5-Fluorouracil
AE:: Auger electrons
ALT:: Alanine aminotransferase
AuNCs:: Gold nanoclusters
AuNPs:: Gold nanoparticles
AuNRs:: Gold nanorods
BC:: Breast cancer
BCM:: Block copolymer micelles
BED:: Biologically effective dose
BLI:: Bioluminescence
BMEDA:: N,N-Bis(2-Mercaptoethyl)-N′,N′-Diethylethylenediamine
CBC:: Complete blood cell
CCS:: Canadian cancer society
CE:: Internal conversion electrons
CED:: Convection enhanced delivery
CEPA:: 3-Phosphonopropionic acid
CHO:: Chinese hamster ovary
CHX-DTPA:: Cyclohexane-1,2-diethylenetriaminepentaacetic acid
cis-Pt:: Cisplatin
cMORF:: Complementary morpholino oligonucleotides
CNCs:: Cellulose nanocrystals
CNT:: Carbon nanotubes
Cr:: Creatinine
CREATE:: Collaborative research and training experience
cRGD:: Cyclic arginine-glycine-aspartic acid
CS:: Clonogenic survival
CSC:: Cancer stem cell
CT:: Computed tomography
CXCL12:: C-X-C motif chemokine 12
CXCR4:: C-X-C chemokine receptor type 4
Cys:: Cysteine
D₁₀ :: Dose required to decrease the surviving fraction of cells to 0.10
DAMP:: Damage-associated molecular patterns
DARP:: Designed ankyrin repeat protein
DEF:: Dose-enhancement factor
DFO:: Desferrioxamine
DLS:: Dynamic light scattering
DMSA:: Dimercaptosuccinic acid
DOTA:: 1,4,7,10-Tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid
Dox:: Doxorubicin
DPK:: Dose-point kernel
DRT:: Dual receptor-targeted
DSB:: Double stranded breaks
DTPA:: Diethylenetriamine pentaacetate
DTT:: Dithiothreitol
DVH:: Dose-volume histograms
DXR:: Doxorubicin
EC:: Electron capture
EGF:: Epidermal growth factor
EGFR:: Epidermal growth factor receptor
EMA:: European medicines agency
EPR:: Enhanced permeability and retention
EUD:: Effective uniform dose
EUD:: Equivalent uniform dose
FAP:: Fibroblast activation protein
FDA:: Food and drug administration
FDG:: Fluorodeoxyglucose
FR-α:: Folate receptor alpha
G4 PAMAM:: Generation 4 poly(amidoamine) dendrimer
GBM:: Glioblastoma multiforme
G-CSF:: Granulocyte colony-stimulating factor
GIP:: Glucose-dependent insulinotropic polypeptide
G_MI :: Monosialoganglioside
GMP:: Good manufacturing practices
GRP:: Gastrin releasing peptide
GRPR:: Gastrin releasing peptide receptor
GSH:: Glutathione
HER2:: Human epidermal growth factor receptor-2
HNSCC:: Head and neck squamous cell carcinoma
HYNIC:: Hydrazinonicotinic acid
i.p. :: Intraperitoneal
ISO:: International organization for standardization
i.t. :: Intratumoral
i.v.:: Intravenous
ID:: Injected dose
iFAP:: Fibroblast activation protein inhibitor
IgG:: Immunoglobulin G
IONPs:: Iron oxide nanoparticles
iPSMA :: Prostate-specific membrane antigen inhibitor
KLH:: Keyhole limpet hemocyanin
LA:: Lipoic acid
LD₅₀ :: Lethal dose-50%
LET:: Linear energy transfer
Lipo-Dox :: Liposomal doxorubicin
LN:: Lymph node
LNC:: Lipid nanocapsules
MC:: Monte carlo
MCF:: Mangiferin
MCNP:: Monte carlo N-particle software
MCP:: Metal-chelating polymers
MIONP:: Magnetic iron oxide nanoparticles
MIRD:: Medical internal radiation dose
MLV:: Multi-lamellar vesicles
MMP:: Matrix metalloproteinases
MPS:: Mononuclear phagocyte system
MRI:: Magnetic resonance imaging
MTD:: Maximum tolerated dose
MTX:: Methotrexate
MUVEL:: Multivesicular liposomes
Nano-RER:: Nano-radio enhancement ratio
^NatLu₂O₃ :: Natural lutetium oxide
NaA:: Zeolite A sodium
NaYF₄ :: Sodium yttrium fluoride
NCs:: Nanocapsules
NDEF:: Nuclear dose enhancement factor
NHS:: N-hydroxysuccinimide
nIR:: Near infrared
NLS:: Nuclear translocation sequence
NMRI:: Naval medical research institute
NOD/SCID:: Non-obese diabetic/severe combined immunodeficiency disease
NP:: Nanoparticles
NPD:: Nanoparticle depot
NRG:: NOD-Rag2-IL2rγTm1/Rj
OPSS:: Orthopyridyldisulphide
p.i. :: Post-injection
PBS:: Phosphate buffered saline
PCL:: Poly-caprolactone
PD-L1:: Programmed cell death ligand-1
PE:: Photoelectrons
PE40:: Pseudomonas exotoxin
PEG:: Poly ethelyne glycol
PET:: Positron emission tomography
POND:: Polymer nanoparticles for drug delivery
p-SCN-Bn-DTPA:: S-2-(4-Isothiocyanatobenzyl)-diethylenetriamine pentaacetic acid
PSMA:: Prostate specific membrane antigen
PTT:: Photothermal therapy
RBE:: Radiobiological effectiveness
RCP:: Radiochemical purity
RER:: Radio enhancement ratio
RGD:: Arginine-glycine-aspartic acid peptide
RNP:: Radionuclide purity
ROS:: Reactive oxygen species
s.c.:: Subcutaneous
SA:: Specific activity
SCN:: Benzyl isothiocyanate
SPECT:: Single photon emission computed tomography
SPION:: Superparamagnetic iron oxide nanoparticles
SPN:: Semiconducting polymer nanoparticles
SRT:: Single-receptor targeted
SUV:: Small unilamellar vesicles
SVA:: Hydroxysuccinimide valerate
SWCNT:: Single walled carbon nanotubes
Tat:: Transactivation of transcription
VEGF:: Vascular endothelial growth factor
WBC:: White blood cell
XRT:: X-radiation therapy
α-MSH:: α-Melanocyte stimulating hormone
γH2AX:: Phosphorylated histone-2AX

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Funding

Research on radiation nanomedicines in the authors laboratory was supported by grants from the Brain Tumour Foundation of Canada, the Canadian Cancer Society (CCS), and the Natural Sciences and Engineering Research Council of Canada (NSERC). Funds were donated to the CCS by the World Gold Council in support of this research. C.J.G. was a scholar of the Terry Fox Foundation Strategic Training and Transdisciplinary Radiation Science for the 21st Century (STARS21) program. C.J.G. was also supported by the NSERC Polymer Nanoparticles for Drug Delivery (POND) Collaborative Research and Training Experience (CREATE) program. C.J.G. and M.K.B. received MDS Nordion Graduate Scholarships in Radiopharmaceutical Sciences.

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Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada
Raymond M. Reilly, Constantine J. Georgiou, Madeline K. Brown & Zhongli Cai
Princess Margaret Cancer Centre, Toronto, ON, Canada
Raymond M. Reilly
Department of Medical Imaging, University of Toronto, Toronto, ON, Canada
Raymond M. Reilly
Joint Department of Medical Imaging, University Health Network, Toronto, ON, Canada
Raymond M. Reilly
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, M5S 3M2, Canada
Raymond M. Reilly

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Raymond M. Reilly
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Constantine J. Georgiou
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Madeline K. Brown
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Zhongli Cai
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R.M.R. conceived of the article design and edited the final manuscript. R.M.R., C.J.G. M.B. and Z.C. researched the literature and drafted the manuscript. All authors reviewed and approved the final manuscript.

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Reilly, R.M., Georgiou, C.J., Brown, M.K. et al. Radiation nanomedicines for cancer treatment: a scientific journey and view of the landscape. EJNMMI radiopharm. chem. 9, 37 (2024). https://doi.org/10.1186/s41181-024-00266-y

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Received: 31 January 2024
Accepted: 22 April 2024
Published: 04 May 2024
DOI: https://doi.org/10.1186/s41181-024-00266-y

Radiation nanomedicines for cancer treatment: a scientific journey and view of the landscape

Abstract

Background

Main body

Conclusions

Background

Main text

Scientific journey: the beginning

Landscape: gold nanoparticles as radiosensitizers of XRT

Journey: HER2-targeted AuNPs for XRT radiosensitization

Journey: radiation nanomedicine for HER2-positive BC

Landscape: NPs labeled with AE-emitting radionuclides

Indium-111

Technetium-99 m

Iodine-125, Palladium-103 and Platinum-193m/195m

Journey: 177Lu-labeled radiation nanomedicines

Landscape: NPs labeled with β-particle emitting radionuclides

Lutetium-177

Gold nanoparticles (AuNPs)

Micelles, polymers and dendrimers

Cellulose nanocrystals

Inorganic NPs

Neutron-activated lutetium oxide NPs

Rhenium-186

Rhenium-188

Yttrium-90

Gold-198

Other β-particle emitting radionuclides

Journey: nanoparticle depot for i.t. delivery of 90Y-labeled NPs

Landscape: radiation dosimetry of radiation nanomedicines

Nanoscopic and microscopic dose deposition

Journey: 177Lu-Labeled NPs for treatment of GBM

Landscape: radiation nanomedicines for GBM

Landscape: NPs labeled with α-particle emitting radionuclides

Actinium-225

Other α-particle emitters

Landscape: future clinical translation of radiation nanomedicines

Regulatory guidelines for nanomedicines

Conclusions

Availability of data and materials

Abbreviations

References

Acknowledgements

Funding

Author information

Authors and Affiliations

Contributions

Corresponding author

Ethics declarations

Ethics approval and consent to participate

Consent for publication

Competing interests

Additional information

Publisher's Note

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About this article

Cite this article

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Keywords

Journey: ¹⁷⁷Lu-labeled radiation nanomedicines

Journey: nanoparticle depot for i.t. delivery of ⁹⁰Y-labeled NPs

Journey: ¹⁷⁷Lu-Labeled NPs for treatment of GBM