Injectable Click Polypeptide Hydrogels via Tetrazine-Norbornene Chemistry for Localized Cisplatin Release

Abstract

Injectable, covalently cross-linked hydrogels have been widely investigated in drug delivery systems due to their superior mechanical properties and long-term stability. Conventional covalently cross-linked hydrogels are formed by chemical reactions that may interfere with natural biochemical processes. In this work, we developed an injectable polypeptide hydrogel via an inverse electron demand Diels-Alder reaction between norbornene modified poly(L-glutamic acid) (PLG-Norb) and tetrazine functionalized four-arm poly(ethylene glycol) (4aPEG-T) for localized release of cisplatin (CDDP). The rapid and bioorthogonal click reaction allowed for hydrogel formation within a few minutes after mixing the two polymer solutions in phosphate buffer saline (PBS). Dynamic mechanical analysis suggested that the storage modulus of the hydrogel could be readily tuned by changing the polymer concentration and the molar ratio of the two functional groups. The carboxyl groups of PLG-Norb were used to form polymer–metal complexation with CDDP, and the controlled release of the antitumor drug was achieved in PBS. The CDDP-loaded hydrogel displayed an antitumor effect against MCF-7 cells in vitro, through S phase cell cycle arrest. After subcutaneous injection in rats, the hydrogel was rapidly formed in situ and showed good stability in vivo. In an MCF-7-bearing nude mice model, the CDDP-loaded hydrogel exhibited an improved antitumor effect with reduced systemic toxicity. Overall, the injectable click polypeptide hydrogel shows considerable potential as a platform for localized and sustained delivery of antitumor drugs.

Hydrolytically Degradable PEG-Based Inverse Electron Demand Diels–Alder Click Hydrogels

“…The spontaneous reaction of Tz/NB iEDDA click chemistry is ideal for biomedical applications owing to its specific and high reactivity under ambient conditions without the need of external stimuli. In particular, this chemistry has been applied for in vivo applications including fluorescent imaging, , ligation of biomolecules, , and injectable, covalently cross-linked hydrogels. ,− Due to the fast gelation time and predictable degradation, we envision PEGNB CA iEDDA click cross-linked hydrogels to be ideal for injectable hydrogel for delivery applications. Due to the degrading matrix, we anticipated a lesser degree of immune response compared to the statically stiff PEGNB hydrogels, consistent with the literature .…”

Engineering Hydrogels for Affinity-Based Release of Therapeutic Proteins

“…PEG is one of the most extensively studied synthetic polymers for the delivery of therapeutic proteins and small molecule drugs − because of its nontoxic, hydrophilic, and relatively bioinert properties. , PEG is polymerized from ethylene oxide in the presence of alkaline catalysts to produce polymers with defined molar mass ranges. PEG-based hydrogels are generally formed from precursors that covalently cross-link by chain-growth or step-growth mechanisms, or a combination of the two .…”

Metal-Free Click-Chemistry: A Powerful Tool for Fabricating Hydrogels for Biomedical Applications

“…The high yield and evolution of a benign byproduct (N 2 gas) make the IEDDA reaction an ideal tool for the fabrication of biocompatible hydrogels, including injectable ones. − In a seminal contribution, Anseth and co-workers utilized the tetrazine-norbornene IEDDA reaction to obtain PEG-based hydrogels suitable for protein patterning and cell encapsulation . A bis-norbornene-functionalized peptide was utilized as a cross-linker to obtain a cell-degradable scaffold.…”