Development and nanotoxicological analysis of hydroxyapatite and calcium phosphate based multifunctional nanoparticles for molecular imaging and therapeutics

Abstract

Multimodal medical imaging deals with combining two or more modalities such as CT, MRI, PET, SPECT and NIR, such that specific information content (anatomical, functional and molecular) from all these methods can be made available to the clinician simultaneously. This will significantly improve the prospects of early stage diagnosis and better disease characterization. However, such an approach demands administration of multimodal contrast agents, i.e.; a single agent that can provide more than one contrast properties simultaneously. In addition, there are also efforts to develop materials that can facilitate combined imaging and therapy, called theragnostics. Therganostics can help in image guided therapy, estimation of therapeutic dose at disease site and real time monitoring of therapy effects. Although nanoparticles are reported to be suitable for providing multifunctional properties, most of the engineered nanoparticles, reported so far, such as quantum dots, silica, iron oxide, possess serious toxicity concerns. Considering this, in this PhD work, we developed a more biocompatible biomineral based hydroxyapatite (HAp) and calcium phosphate (CP) nanoparticles for multimodal imaging and theragnostics. Doping of HAp and CP with clinically approved contrast molecules was carried out to engineer contrast properties for CT, MRI, NIR and nuclear imaging. In the first part, we developed HAp nanoparticles doped with indocyanine green (ICG) and Gd3+ for combined MRI, NIR and X-ray imaging. By aqueous co-precipitation method, ~ 50 nm sized particles were synthesized and optimized the doping concentration at 4.4 at % Gd3+ and 0.03 wt % of ICG (wrt to HAp) for desired magnetic, NIR and CT contrast. In vitro hemocompatibility analysis using primary human blood components such as RBC, platelets, coagulation factors, mononuclear cells, showed that the material is non-toxic upto the tested dose of 200 and#956;g/mL. .....