Thermo-sensitive nanoparticle carrier-based brachytherapy in combination with local chemotherapy makes cancer treatment with high therapeutic effect possible

Introduction: Brachytherapy therapy uses metal-coated radiation sources. For example, on prostate cancer treatment, the seed radiation sources are used, which are permanently inserted into the treatment area. Therefore, we attempted to develop a radiation source that does not need to remain in the body by utilizing biodegradable polymeric nanoparticles. Additionally, polymeric nanoparticles can encapsulate and release various anticancer agents together with therapeutic radioisotopes, so that the combination of brachytherapy and chemotherapy at the local site of nanoparticle injection may improve the therapeutic response compared to conventional brachytherapy. In this study, we designed and synthesized a polymeric nanoparticle-based carriers for radiation source and anticancer drug, which responds to body temperature and stays at the injection site. The developed polymer nanoparticle was locally injected into subcutaneous implanted prostate cancer model mice, and therapeutic effects of the combined brachytherapy and local chemotherapy were evaluated.

Methods: Block polymer consisted of poly(L-lactic acid) and poly(N-n-propylglycine) units was chemically synthesized. Also, poly(L-lactic acid) homopolymer was labeled by β-ray emitting radionuclide of ⁶⁴Cu via chelate moiety. From the mixture of the block polymer, ⁶⁴Cu labeled poly(L-lactic acid) and anticancer drug docetaxel, core-shell type polymer micelle was prepared in ice-cooled aqueous solution. To the BALB/c nu-nu mice transplanted PC-3 tumor cells at the femoral region, the micelle solution was locally injected, and distribution of the injected radioactivity in mice was evaluated using an animal PET system. Also, therapeutic efficacy of the micelle was evaluated by tracing the changes in cancer volume over time.

Results: Poly(N-n-propylglycine), a component of polymeric micelles, is known to show temperature-responsive behavior, which is hydrophilic at temperatures below 20 °C and hydrophobic above 20 °C. The micelles were prepared under ice-cold conditions. The diameter of the polymeric micelles, which was prepared under ice-cooled condition, was approximately 50 nm. By changing the micelle solution temperature to 37 °C, the micelle was quickly formed µm-sized aggregates due to hydrophobization of poly(N-n-propylglycine) units on the polymeric micelle surface. Importantly, at least under the in vitro condition, ⁶⁴Cu was highly stable in the aggregates, but docetaxel was gradually released.

The micelle solution was locally injected into subcutaneously implanted tumor regions. From the animal PET images, radioactivity injected was stably located at the injection site due to the size effect of aggregation, indicating thermo-sensitive micelle developed in this study can be used as a source of radiation for brachy therapy. The combined ⁶⁴Cu brachytherapy and local docetaxel chemotherapy showed high suppressive effect of cancer progression significantly. This might be due to the sustained release of Docetaxel from the micelles working efficiently against tumor cells which could not be removed by ⁶⁴Cu derived β-ray irradiation alone.

Conclusions: Brachytherapy using thermo-sensitive micelles as carriers does not require the radiation source to remain permanently in the body, and can be combined with local anticancer therapy to achieve higher therapeutic efficacy than conventional brachytherapy.