Tumor Microenvironment Sequential Drug/Gene Delivery Nanosystem for Realizing Multistage Boosting of Cancer-Immunity Cycle on Cancer Immunotherapy.

Abstract

The antitumor immune response of cancer immunotherapy is a cascade of cancer-immunity cycles (CIC). The immunosuppression of the tumor microenvironment and low immunogenicity of tumor cells, insufficient T lymphocyte activation, trafficking, and infiltration caused the failure to initiate and run the continuous multistage CIC, leading to unsatisfactory cancer immunotherapy outcomes. A doxorubicin/interleukin-12 plasmid DNA/celecoxib (DOX/pIL-12/CXB) combination strategy was designed by targeting the cascade CIC. Then, an intratumoral CXB-detachable nanosystem, or DOX/PAC/pIL-12 micelleplexes, was developed for sequential drug/gene delivery to facilitate the multistage boosting of CIC on synergistic cancer immunotherapy. The DOX/PAC/pIL-12 micelleplexes could program intratumorally sequential release of CXB to remodulate the tumor microenvironment immunosuppression by suppressing the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) pathway. The smaller sizes and surface charge-switched micelleplexes facilitated the codelivery and corelease of DOX and pIL-12 inside 4T1 tumor cells. These micelleplexes exerted a synergistic antitumor immune response using CIC cascade activation and amplification, providing therapeutic antitumor and antimetastasis efficacy. The drug/gene sequential delivery nanosystem provides a complete CIC-boosted combinatory strategy for developing immunotherapy against cancer.

• Authors: Yongjing Cao, Juan Li, Qiangwei Liang, Jiayu Yang, Xiaojie Zhang, Juntao Zhang, Min An, Jiawei Bi, Yanhua Liu
• Journal: ACS applied materials & interfaces (ACS Appl Mater Interfaces) Vol. 15 Issue 47 Pg. 54898-54914 (Nov 29 2023) ISSN: 1944-8252 [Electronic] United States
• PMID: 37963093 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Pharmaceutical Preparations
• doxorubicin-DNA
• Doxorubicin

Topics

• Humans
• Antineoplastic Agents (pharmacology)
• Pharmaceutical Preparations
• Tumor Microenvironment
• Doxorubicin (pharmacology, therapeutic use)
• Immunotherapy
• Neoplasms (drug therapy)
• Cell Line, Tumor