Abstract

Background: Actinium-225 (225Ac) is receiving major attention as the radionuclide of choice for targeted alpha therapy (TAT) due to its outstanding physical properties such as a long physical half-life of 9.9 days and a short range of alpha (α)-particles which are responsible for the destruction of malignant tumors, whilst sparing normal surrounding tissues. Although the physical properties of 225Ac make it a desirable radionuclide for TAT, its application is challenging due to the lack of chelators available to stabilize its daughter radionuclides, resulting in the recoil effect. This occurs when there is a breakdown between the radionuclide and the chelator, therefore minimizing the therapeutic effects of the radiopharmaceutical. Nanodrug delivery systems (NDDSs) may minimize the challenge of 225Ac’s recoiling daughters and increase tumor penetration. Aim: This study aimed at using poly(lactic-co-glycolic)acid (PLGA) and chitosan (CS) nanoparticles as a delivery vehicle for targeted alpha therapy of prostate cancer in order to increase the therapeutic effect of 225Ac PSMA617-TFA. Methods and Results: PLGA nanoparticles were prepared using a nanoprecipitation method, after which they were functionalized with chitosan and folic acid. Following synthesis of 225Ac PSMA617-TFA, the radiopharmaceutical was loaded onto the nanoparticles. SEM analysis and FTIR were performed for characterization of the nanoparticles, and in-vitro drug release of 225Ac PSMA617-TFA at pH = 6.5 and pH = 7.4, respectively, was measured. The nanoparticles prepared had an average size of 200 nm and had a positive charge. This was further confirmed using a zetasizer and with scanning electron microscope (SEM) analysis. The PLGA-CS nanoparticles indicated a high encapsulation efficiency after 24 h. The results also showed a controlled release of 225Ac PSMA617-TFA over 72 h. The results of this study indicate that PLGA-CS nanoparticles are suitable for retaining 225Ac and its recoiling daughters (221Fr and 213Bi) at the tumor site, potentially providing a platform for future therapeutic evaluation. Conclusions: The results of this study indicate that PLGA-CS nanoparticles demonstrate feasibility as a drug delivery vehicle for 225Ac PSMA617-TFA, with effective retention of 225Ac and its decay daughters. However, biological validation through in vitro cellular studies and in vivo preclinical models is required before therapeutic effectiveness can be established.

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