Injectable Supramolecular Hydrogel for Locoregional Immune Checkpoint Blockade and Enhanced Cancer Chemo-Immunotherapy

Abstract

Immunotherapy has revolutionized the therapeutic modalities of cancer treatment but is severely limited by a low objective response rate and the risk of immune-related side effects. Herein, an injectable supramolecular hydrogel is developed for local delivery of the D PPA-1 peptide (a D-peptide antagonist with a high binding affinity to programmed cell death-ligand 1 (PD-L1)) and doxorubicin (DOX). On the one hand, DOX could kill tumor cells directly and also induce immunogenic cell death to provoke the antitumor immune response. On the other hand, the D PPA-1 peptide could locoregionally block the PD-1/PD-L1 pathway to potentiate T-cell-mediated immune responses and minimize side effects. Eventually, by local injection of this supramolecular hydrogel, the synergistic cancer therapeutic effect was evaluated, showing promise in improving the objective response rate of immunotherapy and minimizing its systemic side effects.

Three-dimensional (3D) scaffolds as powerful weapons for tumor immunotherapy

“…Some chemotherapeutic drugs also induce ICD, during which apoptotic cells release immune-related signals to initiate tumor-specific immune responses [ 167 , 168 ]. Synthetic polymeric scaffolds with prominent physiochemical performances have been developed for immunochemotherapy, lots of which have thermosensitive injectability and stimuli-responsive drug delivery [ 74 , 169 , 170 ]. Qiang Lv et al developed triblock-copolymer hydrogels from poly ( g -ethyl- l -glutamate)-poly (ethylene glycol)-poly ( g -ethyl- l -glutamate) (PELG-PEG-PELG) for local treatment of melanoma [ 171 ].…”

Locally Injectable Hydrogels for Tumor Immunotherapy

“…This immunoregulatory hydrogel system provides a new approach for improving the TME in immunosuppression and enhancing the effect of immunotherapy. In another study, Yang et al [ 65 ] developed a supramolecular hydrogel that encapsulated DOX and D PPA-1, a D-peptide antagonist with high affinity to PD-L1, for combined chemotherapy and immunotherapy. Drug-containing hydrogels injected into the tumor site can gradually release DOX and D PPA-1, which play a synergistic role in enhancing the infiltration of cytotoxic CD8+ T cells in tumors and inducing the secretion of TNF-α and IFN-γ at the highest level.…”

Cryogels: recent applications in 3D-bioprinting, injectable cryogels, drug delivery, and wound healing

“…It has been suggested that cryogels are more suitable for this application, as opposed to hydrogels, as a greater number of cells can be contained within the structure. With an exemption for injectable supramolecular hydrogel systems, which have been demonstrated to perform very well even after injection [74][75][76], hydrogels in general have been cited as being too brittle to enable injection [27]. Injectable cryogels have been investigated as scaffolds, for drug delivery, and for wound-healing applications.…”