Radioprotective Cerium Oxide Nanoparticles: Molecular Imaging Investigations of CONPs’ Pharmacokinetics, Efficacy, and Mechanisms of Action

Author

Philip R. McDonagh III, Virginia Commonwealth UniversityFollow

DOI

https://doi.org/10.25772/RSGK-C791

Defense Date

2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Clinical and Translational Sciences

First Advisor

Jamal Zweit

Second Advisor

Ross Mikkelsen

Abstract

Cerium oxide nanoparticles (CONPs) are being investigated for several anti-oxidant applications in medicine. One of their most promising applications is as a radioprotective drug, an area of research in need due to the severe side effects from radiation therapy. In this work, the potential of CONPs as a radioprotective drug is examined using four criteria: favorable biodistribution/pharmacokinetics, low toxicity, ability to protect normal tissue from radiation damage, and lack of protection of tumor. The mechanisms of action of CONPs are also studied. Biodistribution was determined in radiolabeled CONPs with surface coatings including citrate, dextran T10-amine (DT10-NH₂), dextran T10-polyethylene glycol (DT10-PEG), dextran T10-sulfobetaine (DT10-SB) and poly(acrylic acid) (PAA), and compared to uncoated. ⁸⁹Zr was incorporated into CONPs for positron emission tomography (PET) imaging and ex vivo tissue analysis in tumor bearing mice. Compared to uncoated [⁸⁹Zr]CONPs, coated [⁸⁹Zr]CONPs showed improved biodistribution, including significantly enhanced renal clearance of PAA- [⁸⁹Zr]CONPs. The toxicity of CONPs was evaluated in vitro and in vivo, with low toxicity at therapeutic doses. After clinically mimetic radiation therapy, pre-treatment of mice with coated and uncoated CONPs showed greater than 50% reduction of cell death in normal colon tissue, comparable to the clinically available radioprotective drug amifostine. Tumor control after irradiation of spontaneous colon tumors was unchanged with PAA-CONP pre-treatment, while citrate, DT10-PEG, and uncoated CONP pre-treatment had slightly less tumor control. Xenograft tumors were irradiated after pH normalizing treatment with sodium bicarbonate and PAA-CONP pre-treatment. Treatment of these tumors showed slightly less tumor control than irradiation alone or PAA-CONP plus irradiation, demonstrating that the acidic pH of the tumor microenvironment may be the basis of preventing CONPs’ radioprotective properties in tumor. These studies show that, among the variations of CONPs tested, PAA-CONP shows the most promise for its good biodistribution and quick clearance, low toxicity, ability to protect normal tissue, and lack of protection of tumor, meeting all the criteria set forth for an ideal radioprotective drug. Further studies on the effects of pH on CONPs actions may further elucidate their mechanisms of action, advancing them as a candidate for use as a radioprotective drug during radiation therapy.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

5-13-2016