One-pot synthesis of functional poly(amino ester sulfide)s and utility in delivering pDNA and siRNA

Abstract

The development of efficacious carriers is an important long-standing challenge in gene therapy. In the past few decades, tremendous progress has been made toward non-viral vectors for gene delivery including cationic lipids and polymers. However, there continues to be a need for clinically translatable polymer-based delivery carriers because they offer tunable degradation profiles and functional groups, diverse structures/morphologies, and scalability in preparation. Herein, we developed a library of 144 degradable polymers with varying amine and hydrophobic content via a facile method that involves thiobutyrolactone aminolysis and consequent thiol-(meth)acrylate or acrylamide addition in one-pot. The polymer platform was evaluated for pDNA and siRNA delivery to HeLa cells in vitro. Hydrophobically modified 5S, 2E1, 6CY1, 5CY2, and 2M1 grafted HEMATL polymers are capable of delivering pDNA depending on the chemical composition and the size of the polyplexes. Hydrophobically modified 5S and 2B grafted HEMATL and 5S grafted ATL polymers exhibit capability for siRNA delivery that approaches the efficacy of commercially available transfection reagents. Due to tunable functionality and scalable preparation, this synthetic approach may have broad applicability in the design of delivery materials for gene therapy.

Progress towards the Synthesis of Amino Polyesters via Ring-Opening Polymerization (ROP) of Functional Lactones

“…[32][33][34][35][36] It is worth noting that this mini review has focused exclu-sively on ROP of lactones and the resulting functional polyesters. Reports of functional polymers via step-growth polymerization, [37][38][39][40][41][42] amino functional polycarbonates, [43][44][45][46] and functional lactide derivatives 47,48 have greatly contributed to the field of drug and gene delivery.…”

Introduction to the special issue of Polymer on “Macromolecular Engineering” dedicated to Professor Krzysztof Matyjaszewski on the occasion of his 65th birthday

“…The section starts with Fossum's paper [50] which provides examples of reactivity ratio-controlled polycondensation reactions and their use in the synthesis of functional polyethers. In his paper, Siegwart [51] demonstrates the utility of sequential thiobutyrolactone aminolysis and thiol-ene reactions in the preparation of biodegradable polymers with applications in nucleic acid delivery. Peng's paper [52] describes novel aluminum complexes that mediate stereoselective ring-opening polymerizations.…”

Plin‐amiR, a pre‐microRNA‐based technology for controlling herbivorous insect pests

“…For TK-RNAi to be effective in insects, the dsRNA should be at least 60 bp in length (Bolognesi et al, 2012;Li et al, 2015) and delivered in high quantity (Bally et al, 2018;Mamta and Rajam, 2017). This has been accomplished by expressing dsRNA guided by strong nuclear promoters (Baum et al, 2007;Yan et al, 2015) or from the chloroplast genome (Bally et al, 2016;Jin et al, 2015;Zhang et al, 2015). Recent studies have shown that dsRNA expressed in the chloroplast evades degradation by plant RNAi, accumulates to high levels and can confer protection against the cotton bollworm, Helicoverpa armigera, and the Colorado potato beetle, Leptinotarsa decemlineata (Bally et al, 2016;Jin et al, 2015;Zhang et al, 2015), in tobacco and potato, respectively.…”