Synthesis, characterization and evaluation of 169Yb-labeled tailored hydroxyapatite nanospheres for potential application in nanobrachytherapy

Background The introduction of radiolabeled nanoparticles in the realm of brachytherapy has led to a promising therapeutic strategy for cancer management called ‘nanobrachytherapy’. In the quest of developing a potent radiolabeled inorganic biomaterial for use in nanobrachytherapy, we report the synthesis and evaluation ¹⁶⁹ Yb [T _1/2 = 32.02 d]-labeled glucuronic acid (GA) functionalised hydroxyapatite (HA) nanoparticles (GAHAnp) and established its potency in pre-clinical settings. Results GAHAnp having average hydrodynamic diameter of 45 ± 3 nm was synthesized in house and characterized using various analytical methods. Ytterbium-169 was produced with adequate radionuclidic purity required for medical application by direct neutron activation of isotopically enriched (35.8% in ¹⁶⁸ Yb) Yb target in research reactor. Radiolabeleing protocol of GAHAnp with ¹⁶⁹ Yb to obtain [ ¹⁶⁹ Yb]Yb-GAHAnp in high yield and purity was optimized. Adsorption of [ ¹⁶⁹ Yb]Yb ³⁺ on GAHAnp followed Langmuir-Freundlich isotherm and pseudo-second order kinetics. The mechanism of incorporation of [ ¹⁶⁹ Yb]Yb ^+ 3 on GAHAnp was investigated using density functional theory (DFT) and experimentally verified by radiotracer investigations and XAFS studies. These investigations suggested replacement of Ca ²⁺ with Yb ³⁺ in GAHAnp matrix. The [ ¹⁶⁹ Yb]Yb-GAHAnp formulation demonstrated excellent in vitro radiochemical stability in physiological media and cell toxicity in Raaji cells. SPECT/CT imaging and ex vivo biodistribution carried out after intra-tumoral administration of [ ¹⁶⁹ Yb]Yb-GAHAnp in tumor bearing mice showed near-complete retention of the formulation in the tumor mass upto 2 weeks. Tumor growth could be significantly arrested after administration of 30 MBq dose of the formulation compared to the control. Conclusion Detailed radiochemical and biological investigations reported in this article demonstrate the potential utility of synthesized [ ¹⁶⁹ Yb]Yb-GAHAnp formulation in the treatment of solid tumors through nanobrachytherapy. The formulation exhibited excellent radiochemical stability and significant therapeutic efficacy in pre-clinical models.