Structural Regulation at Poly(ethylene glycol) Termini Facilitates the Formation of Injectable Hydrogels with Modulated Degradation and Release of Biomacromolecules

Abstract

Hydrogels possessing modulated degradation and release behaviors are beneficial for the biological field. However, modulating the degradability and release behavior of a particular class of hydrogels requires a major structural alteration of a cross-linker as well as an adjustment in concentration, both of which affect the initial modulus and gelation kinetics. Herein, we address this shortcoming by a single step installation of a leaving nucleophile at the termini of PEG via the ether (O−CH 2 −Ph−, Cl′-PEG-Cl′) and ester (−Ph−COO−, Cl-PEG-Cl) spacers separately. These two PEG derivatives separately or in combination lead to the rapid formation of hydrogels when combined with a variety of macromolecules with tertiary amine functional group. The hydrogels exhibit a wide variation in degradation properties and time-dependent water swelling depending on the type and proportion of the PEG derivatives. The gelation kinetics is faster when the termini of the PEG derivative contain benzyl chloride groups connected through the ether spacer and is explained by density functional theory. Importantly, the ultimate moduli of the as prepared hydrogels are almost similar irrespective of the termini structure of the PEG derivatives and their proportion. The hydrogels exhibit modulated release profiles of model dextran and bovine serum albumin at pH 7.4. Prolonged delivery of biomacromolecules is achieved with the hydrogel prepared with Cl′-PEG-Cl′ or the combination Cl′-PEG-Cl′+Cl-PEG-Cl. More importantly, hydrogels prepared with Cl′-PEG-Cl′ or the Cl′-PEG-Cl′+Cl-PEG-Cl combination exhibit triggered release (60−100%) of a model protein (isoelectric point ≤ 7.4) and high molecular weight dextran (neutral) at a constant pH of 5 when compared to that at pH 7.4. The key advantages of our design are the access to a library of biological relevant hydrogels from easily available/synthesized amine-functional macromolecules and PEG derivatives with slight variations in the termini structures.

Bioavailability Enhancement Techniques for Poorly Aqueous Soluble Drugs and Therapeutics

“…Recently, amphiphilic block copolymers were developed as a better alternative for the delivery of hydrophobic drugs and therapeutic molecules with enhanced bioavailability. In the amphiphilic block copolymer, the combination of two or more two types (hydrophilic and hydrophobic) of polymeric segments combines and forms amphiphilic copolymers [ 190 , 191 , 192 ]; moreover, these amphiphilic copolymers can be synthesized precisely by different polymerization techniques such as ATRP [ 193 ], RAFT, and radical polymerization [ 194 ]. In these block copolymers [ 195 ], the combination and ratio of the different co-polymeric segments are very important, deciding the efficiency of delivery and bioavailability.…”

Bioavailability Enhancement Techniques for Poorly Aqueous Soluble Drugs and Therapeutics

“…Recently, amphiphilic block copolymers have been developed as a better alternative for the delivery of hydrophobic drugs and therapeutic molecules with enhanced bioavailability. In the amphiphilic block copolymer, the combination of two or more two types (hydrophilic and hydrophobic) of polymeric segments combines and forms amphiphilic copolymers [185][186][187], moreover, these amphiphilic copolymers can be synthesised precisely by different polymerization techniques such as ATRP [188], RAFT, Radical polymerization [189]. In these block copolymers [190] the combination and ratio of the different co-polymeric segments are very important that decide the efficiency of delivery and bioavailability.…”

Physical, Electrochemical, and Solvent Permeation Properties of Amphiphilic Conetwork Membranes Formed through Interlinking of Poly(vinylidene fluoride)-Graft-Poly[(2-dimethylamino)ethyl Methacrylate] with Telechelic Poly(ethylene glycol) and Small Molecular Weight Cross-Linkers

“…Telechelic PEG (Cl-PEG-Cl) with a M n of 4000 g/mol was synthesized (Supporting Information). 44 Synthesis of PVDF-g-PDMAEMA Copolymers via Atom Transfer Radical Polymerization (ATRP). PVDF-g-PDMAEMA copolymers containing low and moderate amounts of PDMAEMA were synthesized by ATRP.…”