Micellar paclitaxel boosts ICD and chemo-immunotherapy of metastatic triple negative breast cancer

Xinyun Qiu; Yan Qu; Beibei Guo; Huan Zheng; Fenghua Meng; Zhiyuan Zhong

doi:10.1016/j.jconrel.2021.12.002

Micellar paclitaxel boosts ICD and chemo-immunotherapy of metastatic triple negative breast cancer

J Control Release. 2022 Jan:341:498-510. doi: 10.1016/j.jconrel.2021.12.002. Epub 2021 Dec 7.

Authors

Xinyun Qiu¹, Yan Qu¹, Beibei Guo¹, Huan Zheng¹, Fenghua Meng², Zhiyuan Zhong³

Affiliations

¹ Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China.
² Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China. Electronic address: fhmeng@suda.edu.cn.
³ Biomedical Polymers Laboratory, College of Chemistry, Chemical Engineering and Materials Science, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou 215123, PR China. Electronic address: zyzhong@suda.edu.cn.

PMID: 34883139
DOI: 10.1016/j.jconrel.2021.12.002

Abstract

Triple negative breast cancer (TNBC) with easy metastasis, "cold" tumor immune microenvironment, and lack of targeted therapy remains poorly prognosed. Chemo-immunotherapy deemed as a potential treatment for TNBC is however confronted by low TNBC selectivity, pronounced systemic toxicity, and limited immunogenic cell death (ICD) induction. Here, employing clinically validated ATN peptide as a ligand and reduction-sensitive biodegradable micelles as a vehicle we constructed α₅β₁ integrin-targeted micellar paclitaxel (ATN-MPTX) to elicit strong and selective ICD and chemo-immunotherapy of TNBC. ATN-MPTX exhibited evident targetability and prominent uptake in α₅β₁ integrin-positive 4 T1 cells and induced significantly stronger ICD than free PTX and non-targeted MPTX. The therapeutic studies in 4 T1 TNBC model demonstrated that ATN-MPTX caused superior tumor accumulation and treatment efficacy to all controls. Of note, ATN-MPTX plus nano-STING agonist further augmented the immunotherapeutic effects by increasing secretion of proinflammatory cytokines and CD4⁺ and CD8⁺ T cells in the tumor and spleen while reducing T_reg, leading to significantly improved inhibition of 4 T1 primary tumor and more interestingly mitigated lung metastases. This strong and selective ICD induction of ATN-MPTX renders it an interesting tool to enhance chemo-immunotherapy of TNBC.

Keywords: Immunoadjuvant; Immunogenic cell death; Micelles; Targeted delivery; Triple negative breast cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes
Humans
Immunogenic Cell Death
Immunotherapy
Paclitaxel / pharmacology
Paclitaxel / therapeutic use
Triple Negative Breast Neoplasms* / drug therapy
Triple Negative Breast Neoplasms* / pathology
Tumor Microenvironment

Substances

Paclitaxel