Date of Award

2024-05-01

Degree Name

Doctor of Philosophy

Department

Environmental Sciences

Advisor(s)

Md M. Nurunnabi

Abstract

Apoptosis, the programmed death of cells, is primarily regulated by a delicate balance between pro-apoptotic and anti-apoptotic signals. The Bcl-2 (B-cell lymphoma 2) family of proteins acts as anti-apoptotic agents, promoting cell survival. Dysregulation of these proteins is a common occurrence in conditions such as cancer and fibrosis, where overexpression of anti-apoptotic members can foster tumor cell survival and fibroblast activation. In this study, our aim was to explore the therapeutic potential of Bcl-2 inhibitors, both as a small molecule (specifically Navitoclax (Navi)), inhibitor and as Bcl-2 siRNA, for targeted treatment. Intravenous administration of Navi often leads to thrombocytopenia, necessitating a precise delivery strategy to the diseased site while maintaining therapeutic efficacy and minimizing side effects. Our initial project focused on utilizing PLGA-based nanoparticles conjugated with Angiotensin 2 (AT2), a protein commonly overexpressed in kidney disease, to achieve targeted delivery. Intravenous administration of Navi-loaded, AT2-conjugated PLGA nanoparticles demonstrated selective kidney targeting without inducing thrombocytopenia. Histological analysis revealed a reversal of fibrosis post-treatment with targeted nanoparticles, corroborated by improved renal function and apoptosis induction in kidney tissues. Encouraged by these findings, our subsequent endeavor involved advancing the delivery system for Bcl2 siRNA in stomach cancer. While siRNA holds promise for cancer therapy due to its ability to target specific genes, oral delivery remains challenging due to instability in the intestinal environment. To address this, we employed β-Glucan (BG), a mucoadhesive polymer, to shield and stabilize siRNA orally. In vivo studies in a stomach cancer mouse model demonstrated that BG-mediated siRNA formulations effectively reduced Bcl2 expression and induced apoptosis, offering a promising avenue for cancer treatment. In conclusion, our findings underscore the potential of targeted delivery systems for Bcl-2 inhibitors in cancer and fibrosis therapy, providing a safe and effective means of inducing apoptosis at disease sites.

Language

en

Provenance

Received from ProQuest

File Size

128 p.

File Format

application/pdf

Rights Holder

Humayra Afrin

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