Multiresponsive Hyaluronan‐p(NiPAAm) “Click”‐Linked Hydrogels

Abstract

Combined reversible addition-fragmentation chain transfer (RAFT) and chemoselective "click" chemistry are used for assembling two polymeric chains into a hybrid network capable to respond simultaneously or separately to different external stimuli. An azido-derivative of hyaluronate is clicked together with a new telechelic RAFT-generated p(NiPAAm), carrying a propargyl function at both ends, suitable as macromolecular "clickable" cross-linker with controlled molecular weight. This hybrid system displays a multiresponsive behavior versus temperature, pH, and ionic strength, maintaining cumulative as well as separate sensitivities to the external stimuli. Hyaluronidase catalyzed degradation of the hydrogels, mimicking the extracellular matrix degradation process, is an additional asset for the use of this class of hydrogels as scaffold. Tumor cells, HT-29, grow on the surface of these hybrid hydrogels more than the healthy ones, as NIH3T3. This finding opens a road to micro- and nano-devices based on hyaluronic acid as a promising biopolymer to pursue localized drug delivery.

Preparation of Well-Defined Propargyl-Terminated Tetra-Arm Poly(N-isopropylacrylamide)s and Their Click Hydrogels Crosslinked with β-cyclodextrin

“…They ascribed this abnormal founding to the chelation of acrylamide groups to copper ions [21], but we think a more important reason might be the influence of molecular structures, especially for the microenvironment near acetylene and azide moieties. After all, most CuAAC PNIPA hydrogels had successfully adopted CuSO 4 /ascorbic acid system [23,40,41].…”

“…Then, they explored photo initiated thiol-ene addition to build a PNIPA “model network” using a tetra-arm mercapto propionate molecule to crosslink an α,ω-bis vinyl PNIPA modified from a RAFT PNIPA [22]. Pasale and coworkers fabricated multi-responsive hyaluronan-PNIPA hybrid hydrogels using azido-grafted hyaluronic acid and α,ω-bis propargyl end-capped PNIPAs, which were derived from mono-alkyne ended RAFT PNIPAs and further conversion of another end to alkyne [23]. We have ever prepared a well-defined linear PNIPA carrying pendant azido groups using RAFT polymerization and the following modification, which was click-crosslinked with multi-alkynyl terminated small molecules to get well-defined PNIPA hydrogels [24].…”

Interpenetrating polymer network as a pioneer drug delivery system: a review

“…HA also has some disadvantages like low mechanical properties and human hyaluronidases catalyzed its degradation, and to solve these problems, chemical modification of HA is done specially for its functional groups including groups of amines, glucuronic acid and hydroxyl (primary and secondary). The associated form of HA with temperature-responsive and pH-responsive polymers is extensively used for synthesizing stimulus-responsive SIPN and IPN networks [96,97]. The formation of double cross-linked IPN hydrogels comprises of temperature-sensitive poly(N-isopropylacrylamide) (PNIPAM) and pH-sensitive HA by radical polymerization and Michael edition.…”

Multi-responsive hydrogels for drug delivery and tissue engineering applications

“…‘Click’ chemistries have also been used to cross-link polymeric chains into a hydrogel network for biomedical applications. For example, thermoresponsive PNIPAAm was modified with various functionalities to serve as a cross-linker, then clicked with azido-grafted hyaluronic acid (HA) to create a polymer network [ 61 ]. The resulting hydrogel exhibited a distinct volume phase transition temperature (VPTT) between 32 and 34°C as well as pH-dependent swelling behavior.…”