Evaluation of the effect of colloidal systems on biodistribution of selected prostate cancer radiopharmaceuticals

PhD (Pharmaceutics), North-West University, Potchefstroom CampusIt has been reported that microemulsion (ME) delivery systems provide an opportunity to enhance the bioavailability and efficacy of a therapeutic agent whilst minimising side effects. The prostate-specific membrane antigen (PSMA) targeting agents PSMA-11 and PSMA-617, which accumulate in prostate tumours, allows for [68Ga]Ga3+-radiolabelling and PET imaging of PSMA-expression in vivo. Radiolabelled [68Ga]Ga-PSMA-617 can be encapsulated in a ME delivery system which is hypothesized to enhance its pharmacokinetic properties. This study investigated the synthesis of [68Ga]Ga-PSMA-617 and [68Ga]Ga-PSMA-617 contained within a ME, the toxicity profile, and microPET/CT imaging and biodistribution in PC3 tumour xenograft male BALB/c mice. [68Ga]Ga-PSMA-617 was synthesized in a combined solid phase and solution chemistry strategy. The formulation of [68Ga]Ga-PSMA-617 into a ME was then evaluated for in vitro and in vivo toxicity and biodistribution. The cytotoxicity of [68Ga]Ga-PSMA-617-ME was tested in HEK293 and PC3 cells. [68Ga]Ga-PSMA-617-ME indicated negligible cellular toxicity at different concentrations. HEK293 cells showed a statistically higher tolerance towards the [68Ga]Ga-PSMA-617-ME compared to PC3 cells. [68Ga]Ga-PSMA-617 and [68Ga]Ga-PSMA-617-ME was administered intravenously in BALB/c mice with or without PC3-tumours followed by microPET/CT imaging and ex vivo biodistribution determination. The ex vivo biodistribution in PC3-tumour bearing BALB/c mice showed the highest amounts of [68Ga]Ga-PSMA-617 radioactivity accumulation in the kidneys and the lowest uptake was seen in the brain. Both the [68Ga]Ga-PSMA-617 and [68Ga]Ga-PSMA-617-ME followed an expected clearance profile for small-sized polar radiopharmaceuticals, with predominant renal clearance. The ME did alter the biodistribution pattern of [68Ga]Ga-PSMA-617 but maintained distribution to the kidneys, albeit at statistically significant higher levels. Similarly, encapsulation in the ME may have resulted in delayed uptake into tumours as can be seen from the higher blood pool values. The incorporation of [68Ga]Ga-PSMA-617 into ME was successfully demonstrated and resulted in a stable non-toxic formulation as evaluated by in vitro and in vivo means. Both the [68Ga]Ga-PSMA-617 and [68Ga]Ga-PSMA-617-ME showed enterohepatic metabolism of [68Ga]Ga-PSMA-617.Doctora