Development of 225Ac PSMA617-TFA Poly(Lactic-co-glycolic)acid Nanoparticles and Their Potential Use in Targeted Alpha Therapy

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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 tumours, 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 stabilise its daughter radionuclides, resulting in the recoil effect. This occurs when there is a breakdown between the radionuclide and the chelator, therefore minimising the therapeutic effects of the radiopharmaceutical. Nanodrug delivery systems (NDDS) may minimise the challenge of 225Ac’s recoiling daughters and increase tumour penetration. Aim: This study aimed at using poly(lactic-co-glycolic)acid (PLGA) and chitosan 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 functionalised 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 characterisation of the nanoparticles and in-vitro drug release of 225Ac PSMA617-TFA at pH= 6.5 and pH= 7.4, respectively was done. The nanoparticles prepared were an average size of 200nm and had a positive charge. This was further confirmed using a zetasizer and with Scanning Electron Microscope (SEM) analysis. The PLGA-Chitosan nanoparticles indicated a high encapsulation efficiency after 24 hours. The results also showed a controlled release of 225Ac PSMA617-TFA over 72 hours. The results of this study indicate that PLGA-Chitosan nanoparticles are suitable for retaining 225Ac and its recoiling daughters (221Fr and 213Bi) at the tumour site, potentially increasing the therapeutic potential of 225Ac PSMA617-TFA. Conclusion: PLGA-Chitosan nanoparticles may be a suitable drug delivery vehicle of 225Ac PSMA617-TFA that can deliver into solid tumours and retain the recoiling daughters within the tumour site.

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