Injectable Matrix Metalloproteinase-Responsive Polypeptide Hydrogels as Drug Depots for Antitumor Chemo-Immunotherapy

Area of Science:

• Biomaterials Science
• Cancer Therapy
• Immunology

Background:

• Injectable hydrogels offer potential as drug depots for localized and sustained co-delivery.
• Combined chemo-immunotherapy is a promising strategy for enhanced tumor treatment.

Purpose of the Study:

• To develop a localized chemo-immunotherapeutic strategy using a stimuli-responsive injectable hydrogel.
• To co-load oxaliplatin (chemotherapy) and anti-PD-L1 (immunotherapy) into a matrix metalloproteinase (MMP)-responsive hydrogel.

Main Methods:

• Fabrication of an MMP-responsive poly(L-glutamic acid) hydrogel (MMP-gel).
• Co-loading of oxaliplatin (OXA) and anti-programmed cell death protein ligand 1 (anti-PD-L1) into the MMP-gel.
• In vivo evaluation of the chemo-immunotherapeutic efficacy in a B16F10 melanoma mouse model.

Main Results:

• The MMP-gel demonstrated in situ gelation, local drug retention, and MMP-triggered sustained release.
• OXA-loaded MMP-gel induced immunogenic cell death (ICD) in tumor cells.
• Co-delivery of OXA and anti-PD-L1 via MMP-gel significantly suppressed tumor growth, prolonged survival, and enhanced anti-tumor immune responses (increased CD8+ T cells and M1 macrophages, decreased Treg and M2 macrophages) with low systemic toxicity.
• The treatment also inhibited distal tumor growth in a bilateral-tumor model.

Conclusions:

• The developed hydrogel-based chemo-immunotherapy system is effective for localized and sustained co-delivery of drugs.
• This strategy holds significant potential for improving cancer treatment outcomes by combining chemotherapy and immunotherapy.
• The MMP-responsive hydrogel platform offers a promising approach for advanced localized cancer therapy.