Graduation Date

Fall 12-20-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Dr. Howard E. Gendelman

Second Advisor

Geoffrey Thiele, PhD.

Third Advisor

DJ Murry, PharmD.

Fourth Advisor

Prasanta Dash, PhD.

MeSH Headings

Theranostic, HIV-1, LNPs, Gene delivery, Drug Delivery, Virology, Infectious Diseases, Pharmacology

Abstract

Antiretroviral therapy (ART) is the standard remedy to improve the health-related quality of life of people living with human immunodeficiency virus (HIV). However, limited access to the viral reservoir has significantly hindered its effectiveness in fully eradicating HIV. Therefore, to improve HIV therapy, here we propose a C-C chemokine receptor type 5 (CCR5)-targeted theranostic lipid Based Nanoparticles (LBNPs) to noninvasively track and specifically deliver the antiretroviral drugs (ARVs) to the viral reservoir. A multi-modular radioactive nanoprobe was synthesized and co-encapsulated with rilpivirine (RPV, an ARV) into the LBNP to achieve a theranostic LBNP that can be tracked by positron emission tomographic and 3D-computed tomographic (PET-CT) imaging systems. The CCR5-targeted LBNPs were formulated by microfluidic mixing, and their physicochemical properties were thoroughly analyzed. The cell viability, CCR5-mediated RPV uptake, retention, and a 25-day-long viral suppression efficacy of a single dose of LBNPs were demonstrated in HIV-ADA infected human monocyte-derived macrophages (MDMs), potential HIV reservoir cells. The non-invasive PET-CT imaging system demonstrated the biodistribution of LBNPs in the humanized mice model. We also demeonstrated the tissue distribution of targeted RPV using LBNPs and their higher viral suppression efficiency in the infected Hu-mice. The LBNP safety profile was also evaluated by examining the hematotoxicity and histological abnormality in the major organs of the treated animals. Comprehensively, the study showed a proof-of-concept of CCR5-targeted LBNP to effectively deliver rilpivirine to the HIV reservoirs and substantially suppress the viral growth. This targeting strategy can be further propelled by using a combination of ARVs.

Comments

2024 Copyright, the authors

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