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.
Highlights
Cisplatin (CDDP) is one of the first-line chemotherapeutic agents for the treatment of various types of epithelial malignancy, including head and neck, lung, ovarian, bladder and testicular cancer
The synthetic strategy of poly(L-glutamic acid) (PLG)-Norb and 4aPEG-T is illustrated in Scheme 1
PLG is a well-accepted synthetic polymer for drug delivery owing to its good biocompatibility and degradability [27]
Summary
Cisplatin (CDDP) is one of the first-line chemotherapeutic agents for the treatment of various types of epithelial malignancy, including head and neck, lung, ovarian, bladder and testicular cancer. The major mechanism of action of CDDP has been linked to its ability to covalently bind to the purine bases on the DNA, forming DNA–platinum adducts. This activates multiple signal transduction pathways involved in cell cycle arrest, DNA damage repair, and apoptotic cell death [1,2]. Its clinical outcomes are compromised by severe side effects such as dose-limiting nephrotoxicity, gastrointestinal toxicity, peripheral neuropathy, and ototoxicity [3] To address these issues, controlled drug delivery systems [4], including micelles [5], liposomes [6] and hydrogels [7], have been developed in recent decades to realize the higher drug concentration at tumor sites and the controlled release profile for a prolonged period of time.
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