Tumor microenvironment-responsive micelles assembled from a prodrug of mitoxantrone and 1-methyl tryptophan for enhanced chemo-immunotherapy
Ru Wang,
Nuannuan Li,
Tianyu Zhang,
Yiying Sun,
Xiaoyan He,
Xiaoyan Lu,
Liuxiang Chu,
Kaoxiang Sun
Affiliations
Ru Wang
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Ministry of Education, Yantai University, Yantai, Shandong Province, China
Nuannuan Li
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Ministry of Education, Yantai University, Yantai, Shandong Province, China
Tianyu Zhang
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Ministry of Education, Yantai University, Yantai, Shandong Province, China
Yiying Sun
Yantai Saipute Analyzing Service Co. Ltd, Yantai, Shandong Province, China
Xiaoyan He
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Ministry of Education, Yantai University, Yantai, Shandong Province, China
Xiaoyan Lu
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Ministry of Education, Yantai University, Yantai, Shandong Province, China
Liuxiang Chu
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Ministry of Education, Yantai University, Yantai, Shandong Province, China
Kaoxiang Sun
Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Ministry of Education, Yantai University, Yantai, Shandong Province, China
AbstractMitoxantrone (MX) can induce the immunogenic-cell death (ICD) of tumor cells and activate anti-tumor immune responses. However, it can also cause high expression of indole amine 2, 3-dioxygenase (IDO) during ICD, leading to T-cell apoptosis and a weakened immune response. An IDO inhibitor, 1-methyl tryptophan (1-MT), can inhibit the activity of IDO caused by MX, resulting in enhanced chemo-immunotherapy. Here, MX-1-MT was connected by ester bond which could be broken in an acidic tumor microenvironment. MX-1-MT was combined with polyethylene glycol (PEG) via a disulfide bond which could be reduced by glutathione overexpressed in tumors, thereby accelerating drug release at target sites. Folic acid-modified distearoyl phosphoethanolamine-polyethylene glycol (DSPE-PEG-FA) was introduced to form targeting micelles. The micelles were of uniform particle size, high stability, and high responsiveness. They could be taken-up by drug-resistant MCF-7/ADR cells, displayed high targeting ability, and induced enhanced cytotoxicity and ICD. Due to 1-MT addition, micelles could inhibit IDO. In vivo studies demonstrated that micelles could accumulate in the tumor tissues of nude mice, resulting in an enhanced antitumor effect and few side-effects.
