Graduation Date
Spring 5-10-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Biochemistry & Molecular Biology
First Advisor
David Oupický
Abstract
Lipid nanoparticles (LNPs) have emerged as a powerful platform for the delivery of RNA and small-molecule therapeutics, enabling improved drug stability, biodistribution, and cellular uptake. This study explores the formulation and optimization of LNPs for two distinct therapeutic applications: (1) mRNA-based therapy for pancreatic cancer (PC) and (2) extended-action fostemsavir (FTR) delivery for HIV-1 treatment. For PC therapy, a library of 48 mRNA-LNP formulations was developed for intraperitoneal (IP) administration in an orthotopic pancreatic tumor mouse model. Using microfluidic assembly, LNPs were engineered with varying lipid compositions and characterized based on size, zeta potential, and cytotoxicity. Biodistribution and mRNA expression were tracked using fluorescence-based labeling (RhB-DHPE) and firefly Luciferase mRNA (fLuc mRNA), respectively. Results revealed that specific lipid compositions exhibited preferential accumulation in pancreatic tumors, with distinct correlations between biodistribution and mRNA expression levels. Statistical analyses using JMP software identified key formulation parameters influencing delivery efficiency and therapeutic potential. For HIV-1 therapy, an extended-action FTR-LNP formulation was developed to serve as a long-acting antiretroviral drug depot within monocyte-derived macrophages. The formulation aimed to enhance plasma drug residence time by optimizing physicochemical properties, including PEGylated lipid composition, flow rate ratios, size, polydispersity, shape, and zeta potential. These parameters influenced the LNP’s ability to withstand fluid flow forces, cellular internalization, and antiretroviral efficacy. The FTR-LNP formulation demonstrated stability, efficient macrophage uptake, and extended drug release, highlighting its potential for long-acting HIV-1 therapy. Both studies underscore the critical role of lipid composition and formulation parameters in optimizing LNP-based drug delivery. By mapping the formulation space for both mRNA and small-molecule therapeutics, this research provides insights into the rational design of LNPs for targeted and extended-action drug delivery. These findings contribute to advancing precision nanomedicine for cancer and infectious disease treatments.
Recommended Citation
Islam, Farhana, "Navigating Lipid Nanoparticle Design: From Microfluidic Optimization for RNA Delivery in Pancreatic Cancer to Extended-release Formulations for HIV-1 Therapy." (2025). Theses & Dissertations. 918.
https://digitalcommons.unmc.edu/etd/918
Comments
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