Bisphosphonate-based coordination complexes and immobilization thereof in titanium dioxide nanoparticles

Abstract

Coordination complexes (CCs), as well as inorganic nanoparticles, present several advantages towards nanotechnology-based cancer therapy applications. Both types of materials provide stability, specificity, low cytotoxicity, and the delivery of various therapeutic agents. In this thesis, a material denominated as bisphosphonate-based coordination complex (BPCC) was immobilized in high-purity rutile phase titanium dioxide (TiO₂) nanoparticles to form a functionalized material with suggested potential against osteolytic metastases (OM). Clinically utilized nitrogen-containing bisphosphonates (BPs) named alendronate (ALEN), risedronate (RISE), and zoledronate (ZOLE) were employed, and reacted with three different bioactive metals (M₂₊= Ca₂₊, Mg₂₊, and Zn₂₊), varying synthesis conditions to obtain BPCCs. Assessment of the potential of the resulting materials for biomedical applications was initially performed by decreasing their crystal size to a nano-range employing a phase inversion temperature (PIT)-nano-emulsion method. Other biomedical properties were determined, such as structural stability and aggregation in simulated physiological media, binding affinity to hydroxyapatite (HA), and cytotoxicity against MDA-MB-231 (cancerous model) and hFOB 1.19 (non-cancerous model) cell lines. Polymorphic control of TiO₂ was addressed prior to immobilization of BPCCs. Three novel distinct synthetic routes leading to the formation of TiO₂ were designed employing the PIT-nano-emulsion method. The chemical nature (pH) of the emulsion system and thermal treatment were varied to selectively isolate each one of the three phases of this metal oxide, namely rutile, anatase and brookite. The synthetic route leading to highly-pure rutile (H₂O:HNO₃/Heptane, 850°C) was utilized to obtain TiO₂ nanoparticles for their functionalization with BPCCs. The combination of a selected BPCC, ZOLE-Ca form II, with TiO₂ was achieved through in situ surface crystallization. The hydrothermal reaction of this BPCC was carried out in presence of photoactivated TiO₂ nanoparticles by ultraviolet (UV) irradiation. The reaction time was varied to control crystal growth of the BPCC around the TiO₂ core, resulting in TiO₂-core:nano-Ca@ZOLE-shell nanoparticles. Crystal phase assessment, surface morphology and composition analysis, particle size measurements and cytotoxicity effects of the functionalized particles were performed. Results demonstrated that the designed immobilized system could provide a novel approach to potentiate the therapeutic effects observed for the BPCCs as a multi-drug therapy for treatment and prevention of OM and other bone-related diseases.