Date of Award
Spring 2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biomedical Engineering (ENAS)
First Advisor
Saltzman, W. Mark
Abstract
Fetal therapy is a rapidly expanding field that provides opportunities to treat or prevent congenital diseases early in the process of fetal development. Prior studies suggest that polymeric nanoparticles (NPs) are a safe, tunable, and effective vehicle for in utero delivery of therapeutic agents via administration into the amniotic fluid space. Previous work has focused on the feasibility of using poly(lactic-co-glycolic acid) (PLGA) NPs, as well as viral vectors and lipid NPs, for in utero delivery. Modifications to the core polymer and surface chemistry of NPs are known to be key in modulating the performance of NPs in various biological environments, but these effects are still incompletely understood for in utero applications. In this thesis, the characteristics and delivery profiles for successful in utero administration of polymeric NPs through fetal systemic or amniotic fluid (AF) routes are investigated, including studies of protein corona composition, NP biodistribution, and transfection of genetic material. We found that the protein coronas of NPs in AF can be modulated by varying the core polymer, and the addition of polyethylene glycol (PEG) to the surface stabilizes NPs in AF and makes intra-amniotic (IA) delivery possible. After IA administration, PLGA-PEG and poly(lactic acid)-PEG (PLA-PEG) NPs distributed to the fetal lung and gut,respectively. IA administration of poly(amine-co-ester)-PEG (PACE-PEG) NPs resulted in multi-organ distribution to the fetal lung and liver. We also demonstrated successful biodistribution and mRNA transfection in a fetal non-human primate model after intravenous (IV) administration of PLGA and PACE-PEG NPs. Finally, we explored the potential of PACE polyplexes to deliver mRNA after IV administration and provided a foundation for future in utero optimization of this strategy. Altogether, this thesis supports polymeric NPs as promising candidates for fetal therapeutic delivery vehicles which can be applied in many congenital diseases.
Recommended Citation
Lynn, Anna, "Engineering Polymeric Nanoparticles for Intra-Amniotic and Intravenous In Utero Delivery" (2024). Yale Graduate School of Arts and Sciences Dissertations. 1445.
https://elischolar.library.yale.edu/gsas_dissertations/1445
