Co-delivery of proanthocyanidin and mitoxantrone induces synergistic immunogenic cell death to potentiate cancer immunotherapy.

Abstract

Immunological checkpoint inhibitors provide a revolutionary method for cancer treatment. However, due to low tumor mutations and insufficient infiltration of immune cells into the tumor microenvironment, 85% of colorectal cancer patients cannot respond to checkpoint blockade immunotherapy. In this study, tumor microenvironment-responsive deformable nanoparticles (DMP@NPs) were rationally designed to improve immunotherapy by synergistically modulating the immune tumor microenvironment. DMP@NPs self-assemble from a newly synthesized tumor acidity responsive polypeptide checkpoint inhibitor polymer (PEG-DMA-DPPA-1) with immunogenic cell death (ICD) enhanced combination drugs containing a certain proportion of mitoxantrone (MITX) and proanthocyanidins (PC). Upon tumor acidity-triggered cleavage of PEG-DMA-DPPA-1, DMP@NPs undergo special "sphere-ring deformation" dissociation, gradually releasing polypeptide checkpoint inhibitor DPPA-1, MITX and PC. MITX/PC in vitro synergistically triggers higher ICD with the release of the high mobility group box-1 (HMGB-1) and calreticulin (CRT). After intravenous injection of DMP@NPs, the local tumor microenvironment of CT26 tumor-bearing mice was reprogrammed, and dendritic cell activation and T cell infiltration were significantly increased. Most importantly, the synergistic immune nanodrug DMP@NPs improved the efficacy of colorectal cancer immunotherapy and reduced toxicity and side effects for the immune organs.

• Authors: Ying Qian, Jiarong Mao, Xuejiao Leng, Ling Zhu, Xue Rui, Zhetong Jin, Houzhe Jiang, Heng Liu, Fengguang Zhang, Xiaolin Bi, Zhipeng Chen, Jingjing Wang
• Journal: Biomaterials science (Biomater Sci) Vol. 10 Issue 16 Pg. 4549-4560 (Aug 09 2022) ISSN: 2047-4849 [Electronic] England
• PMID: 35790120 (Publication Type: Journal Article)

Chemical References

• Proanthocyanidins
• Mitoxantrone

Topics

• Animals
• Cell Line, Tumor
• Colorectal Neoplasms (drug therapy)
• Immunogenic Cell Death
• Immunotherapy (methods)
• Mice
• Mitoxantrone (pharmacology)
• Nanoparticles
• Proanthocyanidins (pharmacology)
• Tumor Microenvironment