Hybrid Bioactive Nanoparticles for Modulation of Tumor Microenvironment and Enhancing Radiation and Chemotherapy Efficacy
Year: 2019
Type: dissertation
Abstract: Tumor microenvironment (TME) abnormalities are recognized as the main obstacle in treating solid tumors and are responsible for the failures in cancer therapies via promoting tumor cell growth, invasion, resistance to radiation and chemotherapy (CT), and escape from immune surveillance. To tackle interplay of multiple TME factors, our team has previously designed novel hybrid manganese dioxide nanoparticles (MDNPs) with the high reactivity and specificity toward H2O2 for the simultaneous and sustained production of O2 and regulation of pH to modulate the TME. Here, we propose a new multimodal strategy by utilizing MDNPs to remodel the TME, suppress drug and radiation resistance factors, reverse immunosuppressive conditions, and enhance treatment efficacy. Results from this thesis reveal the high potential of MDNPs in quenching reactive oxygen species (ROS) (e.g. H2O2), decreasing HIF1α, and lowering hypoxia level in the tumor. In comparison to radiation therapy (RT) alone, the combination of MDNPs and RT promoted cell death and decreased cancer cell proliferation in tumor-bearing animals. Survival studies not only resulted in significant increase in median survival time for breast and prostate tumor-bearing animals treated with the combination MDNPs + RT, but also achieved curative III treatment. It was further observed that MDNPs could modulate TME, reflected in downregulation of drug resistance factors and enhanced cellular uptake and anti-cancer activity of doxorubicin (DOX). The combination therapy with MDNPs and DOX also stimulated adaptive antitumor immunity and decreased immunosuppression, resulting up to 60% complete tumor regression in breast tumor-bearing mice. The high in vivo tolerability and stability of the nanoparticles, the simplicity of administration and effectiveness of the MDNPs on CT and RT are key elements that will make this system highly translational. Such results suggest that the new multimodal combination therapies are a simple yet powerful approach to treat solid tumors. Further, it was shown that the polymer-lipid nanoparticle (PLN) formulation developed by our team has a transformable behaviour in physiological condition, enabling higher intracellular uptake in vitro and intratumoral accumulation and penetration in-vivo of DOX when compared to liposomal or free solution of DOX. The findings in this thesis verify that transformable PLN system offers a unique platform and a novel approach for more effective drug transportation to the tumor.
Source: TSpace (University of Toronto)
Author: Mohammad Amini
Language: English
Subfield: Biomedical Engineering
Field: Engineering
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W3187928793