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Sequential Nucleophilic "Click" Reactions for Functional Amphiphilic Homopolymers.

ABSTRACT: Amphiphilic homopolymers with high densities of functional groups are synthetically challenging. Thiol-yne nucleophilic click reactions have been investigated to introduce multiple functional groups in polymers with high density. An electron deficient alkyne group bearing methacrylate monomer was polymerized using reversible addition-fragmentation chain-transfer (RAFT) polymerization. Subsequently, the electron deficient alkyne group on polymer side chain was readily reacted with a thiol reagent using triethylamine (TEA) as the organocatalyst. This reaction was found to be very efficient under mild conditions. The resultant homopolymer bearing thiol vinyl ether functional groups could perform a second thiol addition with a stronger base, such as triazabicyclodecene (TBD), to prepare multifunctional homopolymers. This stepwise addition process was monitored by 1H NMR as well as gel permeation chromatography. The fidelity of this method was demonstrated by attaching four different functionalities, including both hydrophobic and hydrophilic moieties. Furthermore, these dual functionalized polymers bearing dithio-acetal groups are sensitive to reactive oxygen species (ROS), which compromises the host-guest properties of the assembly in response to this stimulus. The ROS responsive polymers reported here may have potential use in therapeutic delivery.

SUBMITTER: He H

PROVIDER: S-EPMC6707748 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Sequential Nucleophilic "Click" Reactions for Functional Amphiphilic Homopolymers.

He Huan H Liu Bin B Wang Meizhe M Vachet Richard W RW Thayumanavan S S

Polymer chemistry 20181115 2

Amphiphilic homopolymers with high densities of functional groups are synthetically challenging. Thiol-yne nucleophilic click reactions have been investigated to introduce multiple functional groups in polymers with high density. An electron deficient alkyne group bearing methacrylate monomer was polymerized using reversible addition-fragmentation chain-transfer (RAFT) polymerization. Subsequently, the electron deficient alkyne group on polymer side chain was readily reacted with a thiol reagent ...[more]

PMID: 31447949

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Project description:Hydrogels with dynamically tunable crosslinking are invaluable for directing stem cell fate and mimicking a stiffening matrix during fibrosis or tumor development. The increases in matrix stiffness during tissue development are often accompanied by the accumulation of extracellular matrices (e.g., collagen, hyaluronic acid (HA)), a phenomenon that has received little attention in the development of dynamic hydrogels. In this contribution, we present a gelatin-based cell-laden hydrogel system capable of being dynamically stiffened while accumulating HA, a key glycosaminoglycans (GAG) increasingly deposited by stromal cells during tumor progression. Central to this strategy is the synthesis of a dually-modified gelatin macromer - gelatin-norbornene-carbohydrazide (GelNB-CH), which is susceptible to both thiol-norbornene photopolymerization and hydrazone click chemistry. We demonstrate that the crosslinking density of cell-laden thiol-norbornene hydrogels can be dynamically tuned via simple incubation with aldehyde-bearing macromers (e.g., oxidized dextran (oDex) or oHA). The GelNB-CH hydrogel system is highly cytocompatible, as demonstrated by in situ encapsulation of pancreatic cancer cells (PCC) and cancer-associated fibroblasts (CAF). This unique dynamic stiffening scheme provides a platform to study tandem accumulation of HA and elevation in matrix stiffness in the pancreatic tumor microenvironment. STATEMENT OF SIGNIFICANCE: Hydrogels permitting on-demand and secondary crosslinking are ideal for mimicking a stiffening tumor microenvironment (TME). However, none of the current dynamic hydrogels account for both stiffening and accumulation of hyaluronic acid (HA), a major extracellular matrix component increasingly deposited in tumor stromal tissues, including pancreatic ductal adenocarcinoma (PDAC). The current work addresses this gap by developing a dynamic hydrogel system capable of simultaneously increasing stiffness and HA accumulation. This is achieved by a new gelatin macromer permitting sequential thiol-norbornene (for primary network crosslinking) and hydrazone click chemistry (for bioinert or biomimetic stiffening with oxidized dextran (oDex) or oHA, respectively). The results of this study provide new insights into how dynamically changing physicochemical matrix properties guide cancer cell fate processes.

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Sequential Nucleophilic "Click" Reactions for Functional Amphiphilic Homopolymers.

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Sequential Nucleophilic "Click" Reactions for Functional Amphiphilic Homopolymers.

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