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Poly(β-aminoester) Physicochemical Properties Govern the Delivery of siRNA from Electrostatically Assembled Coatings

Author(s)
Berger, Adam G; DeLorenzo, Charles; Vo, Chau; Kaskow, Justin A; Nabar, Namita; Hammond, Paula T; ... Show more Show less
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Abstract
Localized short interfering RNA (siRNA) therapy has the potential to drive high-specificity molecular-level treatment of a variety of disease states. Unfortunately, effective siRNA therapy suffers from several barriers to its intracellular delivery. Thus, drug delivery systems that package and control the release of therapeutic siRNAs are necessary to overcome these obstacles to clinical translation. Layer-by-layer (LbL) electrostatic assembly of thin film coatings containing siRNA and protonatable, hydrolyzable poly(β-aminoester) (PBAE) polymers is one such drug delivery strategy. However, the impact of PBAE physicochemical properties on the transfection efficacy of siRNA released from LbL thin film coatings has not been systematically characterized. In this study, we investigate the siRNA transfection efficacy of four structurally similar PBAEs in vitro. We demonstrate that small changes in structure yield large changes in physicochemical properties, such as hydrophobicity, pKa, and amine chemical structure, driving differences in the interactions between PBAEs and siRNA in polyplexes and in LbL thin film coatings for wound dressings. In our polymer set, Poly3 forms the most stable interactions with siRNA (Keff,w/w = 0.298) to slow release kinetics and enhance transfection of reporter cells in both colloidal and thin film coating approaches. This is due to its unique physiochemical properties: high hydrophobicity (clog P = 7.86), effective pKa closest to endosomal pH (pKa = 6.21), and high cooperativity in buffering (nhill = 7.2). These properties bestow Poly3 with enhanced endosomal buffering and escape properties. Taken together, this work elucidates the connections between small changes in polymer structure, emergent properties, and polyelectrolyte theory to better understand PBAE transfection efficacy.
Date issued
2024-04-30
URI
https://hdl.handle.net/1721.1/160557
Department
Koch Institute for Integrative Cancer Research at MIT; Harvard-MIT Program in Health Sciences and Technology; Massachusetts Institute of Technology. Institute for Soldier Nanotechnologies; Massachusetts Institute of Technology. Department of Chemical Engineering; Broad Institute of MIT and Harvard
Journal
Biomacromolecules
Publisher
American Chemical Society
Citation
Adam G. Berger, Charles DeLorenzo, Chau Vo, Justin A. Kaskow, Namita Nabar, and Paula T. Hammond. Biomacromolecules 2024 25 (5), 2934-2952.
Version: Author's final manuscript

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