Membranotropic Peptide-Functionalized Poly(lactide)-graft-poly(ethylene glycol) Brush Copolymers for Intracellular Delivery

Abstract

A biodegradable delivery scaffold based on poly(lactide)-graft-poly(ethylene glycol) (PLA-g-PEG) is introduced and tested in vitro. The use of a functional ring-opening polymerization initiator (containing a masked aldehyde) on an azido PEG-lactide monomer combines two known methodologies to afford functionalized PLA. The resulting copolymer features two compatible functional groups and decreased hydrophobicity due to the PEG. The functional groups are capable of performing high-yielding orthogonal postpolymerization reactions, namely strain-promoted azide-alkyne click chemistry and reductive amination. PLA-g-PEG was functionalized with a fluorescent dye (7-nitrobenzoxadiazole, NBD) and a cell internalization peptide, gH625. The resulting delivery vehicle was investigated for cell uptake with HeLa cells, showing that the gH625 conjugation exhibited enhanced cellular uptake and localization in close proximity to the nuclei. The presented methodology is a new approach toward targeted delivery

Functional biodegradable polymers via ring-opening polymerization of monomers without protective groups

“…Overall yields for the synthetic strategy of A58-A60 were 6-16%. Weck and coworkers 139 introduced an azido-tri(ethylene glycol) functional lactide (A61). Polymers were modified with a fluorescent dye (7-nitrobenzoxadiazole, NBD) and a cell internalization peptide gH625 by click chemistry, and proved cellular uptake.…”

<em>Daphnia magna</em> and<em> Xenopus laevis</em> as in vivo models to probe toxicity and uptake of quantum dots functionalized with gH625

“…10,11 This peptide has proved to exhibit exceptional vector properties 9 and has been shown to be essentially internalized by a nonendocytic pathway avoiding endosomal entrapment. 7,[12][13][14][15][16][17] In recent studies, it was also shown to be able to cross the blood-brain barrier in vitro and in vivo. 18 gH625 is, therefore, a very good delivery vector 9 and its coupling to NPs may be exploited to change their internalization mechanism and in case of MNPs, to avoid or reduce their toxicity.…”

Thio‐bromo “Click,” post‐polymerization strategy for functionalizing ring opening metathesis polymerization (ROMP)‐derived materials

“…This has led to the development and use of alternative, metal‐free click strategies. Diels‐Alder, strain‐promoted cycloadditions, and thiol/ene reactions have all been used with respect to polymer functionalization. Dove and coworkers have recently utilized all three of these reactions in an orthogonal, one‐pot, postpolymerization strategy for the preparation of functional polycarbonates …”