Thermosensitive Polymer Micelles as Radiation Source Carriers for Brachytherapy Enable Effective Combined Therapy with Local Anti-cancer Drugs

Abstract

Polymeric nanoparticles are known for their ability to encapsulate and release various compounds. We hypothesized that encapsulating anti-cancer drugs alongside therapeutic radionuclides could enable combination therapy using brachytherapy and localized chemotherapy. This study was aimed at developing biodegradable polymer-based nanocarriers that can serve as a radiation source for brachytherapy and determining whether this combination of brachytherapy and chemotherapy could offer a higher therapeutic response than conventional brachytherapy. A block polymer consisting of poly(l-lactic acid) and poly(N-n-propylglycine) units was chemically synthesized. Additionally, a poly(l-lactic acid) homopolymer was labeled with the β-ray-emitting radionuclide ⁶⁴Cu via a chelating moiety. Using a mixture of the block polymer, ⁶⁴Cu labeled poly(l-lactic acid), and the anti-cancer drug docetaxel, we prepared a core–shell-type polymer micelle in an ice-cooled aqueous solution. This micelle solution was locally injected into the tumor region of mice, and radioactivity distribution was evaluated using an animal positron emission tomography system. Therapeutic efficacy was assessed by monitoring changes in tumor volume over time. The block polymer exhibited thermodynamic behavior, forming micelles in ice-cold conditions. When the temperature of the micelle solution was raised, µm-sized aggregates formed rapidly at 25–30 °C due to the hydrophobization of poly(N-n-propylglycine) units on the micelle surface. Importantly, ⁶⁴Cu remained stable within the aggregates, while docetaxel was gradually released. After the local injection of the micelle solution into subcutaneously implanted tumors, radioactivity was stably detected at the injection site. The combination of ⁶⁴Cu brachytherapy and localized docetaxel chemotherapy significantly suppressed cancer progression compared to either ⁶⁴Cu brachytherapy or docetaxel chemotherapy alone. The thermosensitive micelles developed in this study can be used as a radiation source for brachytherapy, eliminating the need for permanent metal seed insertion. Moreover, combining local anti-cancer therapy with brachytherapy offers higher therapeutic efficacy than conventional brachytherapy alone.