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Impact of Cationic Charge Density and PEGylated Poly(amino acid) Tercopolymer Architecture on Their Use as Gene Delivery Vehicles. Part 1: Synthesis, Self-Assembly, and DNA Complexation.

David Ulkoski,C. Scholz

Published 2018 in Macromolecular Bioscience

ABSTRACT

The interaction of PEGylated poly(amino acid)s with their biological targets depends on their chemical nature and spatial arrangement of their building blocks. The synthesis, self-assembly, and DNA complexation of ABC terblock copolymers consisting of poly(ethylene glycol), (PEG), poly(l-lysine), and poly(l-leucine), are reported. Block copolymers are produced by a metal-free, living ring-opening polymerization of respective amino acid N-carboxyanhydrides using amino-terminated PEG as macroinitiator: (PEG-b-p(l-Lys)x -b-p(l-Leu)y , PEG-b-p(l-Leu)x -b-p(l-Lys)y , and PEG-b-p((l-Lys)x -co-p(l-Leu)y ). Sizes of self-assembled nanoparticles depend on the formation method. The nanoprecipitation method proves useful for copolymers with the poly(l-lysine) block protected as trifluoroacetate, effective diameters range between 92 and 132 nm, while direct dissolution in distilled water is suitable for the deprotected copolymers, yielding effective diameters between 52 and 173 nm. Critical micelle concentration (CMC) analyses corroborate particle size analyses and show a distinct impact of the molecular architecture; the lowest CMC (8 µg mL-1 ) is observed when the poly(l-leucine) segment forms the C-block and the hydrophilic, disassembly driving poly(l-lysine) segment is short. DNA complexation, evaluated by gel motility and RiboGreen analyses, depends strongly on the molecular architecture. A more efficient DNA complexation is observed when poly(l-lysine) and poly(l-leucine) form individual blocks as opposed to them forming a copolymer.

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