Graduation Date

Spring 5-6-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

David Oupicky, Ph.D.

Second Advisor

Robert Bennett, Ph.D.

Third Advisor

Benita McVicker, Ph.D.

Fourth Advisor

Martin Conda-Sheridan, Ph.D.

Abstract

Alcohol-associated liver disease (AALD) is a major cause of liver disorders worldwide. Current treatment options are limited, especially for AALD-related fibrosis. Targeted therapies are urgently needed for severe forms of AALD. In my project, dual-functioning nanoparticles for the effective delivery of antifibrotic RNA were designed and developed, together with combined CXCR4 inhibition or CD44 targeting as a way to improve the treatment of AALD fibrosis. An alcoholic fibrosis model of moderate alcohol consumption with secondary liver insult was built for evaluation of nanoparticle performance in vivo. In Chapter 2, a cholesterol-modified polymeric CXCR4 inhibitor (Chol-PCX) was synthesized and used to encapsulate anti-miR-155. Treatment with the Chol-PCX/anti-miR-155 particles resulted in significantly reduced aminotransferase enzymes as well as collagen content in the liver parenchyma. In Chapter 3, hyaluronic acid-cyclam (HA-C) nanoparticles with CXCR4 and CD44 dual targeting ligands were fabricated to provide an improved biodistribution in AALD. HA-C nanoparticles represent a promising active targeting strategy to deliver nucleic acids to fibrogenic activated HSC (aHSCs), while reducing the uptake to the mononuclear phagocyte system (MPS), therefore, maximizing the therapeutic effect of antifibrotic RNAs. In Chapter 4, biomimetic macrophage membrane-camouflaged miRNA nanocarriers (MP) were formulated. The MP keep the bioactive function of the source macrophage while enabling a prolonged nanoparticle blood circulation time by evading mononuclear phagocytotic system/reticuloendothelial system (MPS/RES), thus, enhancing the nucleic acids delivery to AALD. In conclusion, polymer-based nanoparticles can enhance delivery of nucleic acids to AALD mice and exert antifibrotic effects.

Comments

2023 Copyright, the authors

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