Bacterial microbots for acid-labile release of hybrid micelles to promote the synergistic antitumor efficacy.

Abstract

Bacteria have inherent properties of self-propelled navigation and specific infiltration into solid tumors. In the current study, we investigate a novel type of bacterial microbots for delivery of hybrid micelles to promote the synergistic antitumor efficacy. Escherichia coli Nissle 1917 (EcN) is used as a bacterial carrier to immobilize amphiphilic copolymers through acid-labile 2-propionic-3-methylmaleic anhydride (CDM) linkers. Doxorubicin (DOX) and α-tocopheryl succinate (TOS) are conjugated with poly(ethylene glycol) through disulfide linkers to obtain amphiphilic promicelle polymers (PMTOS and PMDOX). Tetrazine and norbornene terminals are grafted on EcN and PMTOS/PMDOX copolymers, respectively, and the mild and site-specific bioorthogonal reaction between them maintains the viability, motion ability, and tumor accumulation capability of the conjugated EcN. The PMTOS/PMDOX copolymers are released from bacterial microbots in response to the slightly acidic tumor microenvironment, followed by in situ formation of these copolymers as hybrid micelles (MD/T). The self-assembled micelles from PMTOS/PMDOX with a ratio of 1:2 demonstrate the most significant synergistic efficacy, and the released MD/T hybrid micelles exhibit cellular uptake efficiency, glutathione (GSH)-sensitive drug release, and cytotoxicities similar to those exhibited by micelles prepared by solvent evaporation. Because of the consecutive process of the self-propelling nature of bacteria and preferential accumulation of EcN in tumors, in situ formation of MD/T hybrid micelles, and intracellular drug release, bacterial microbots have shown remarkable antitumor efficacy with regard to animal survival, tumor growth, and apoptosis induction in tumor cells. Therefore, we demonstrate a feasible strategy for the construction of bacterial microbots to achieve tumor accumulation and on-demand release of multiple therapeutic agents for synergistic antitumor efficacy.

STATEMENT OF SIGNIFICANCE:

Challenges remain in the targeted delivery of nanoparticles to solid tumors and the realization of synergistic efficacy in cancer chemotherapy. In the current study, we explore a novel class of bacterial microbots to load, deliver, and release hybrid micelles. Escherichia coli Nissle 1917 (EcN) is used as a bacterial carrier to immobilize amphiphilic copolymers through acid-labile linkers, and the released copolymers are self-assembled into micelles. The resulting bacterial microbots integrate self-propelling bacteria and self-assembling amphiphilic polymers into micelles and realize pH-responsive release of promicelle polymers from bacterial microbots and glutathione-responsive intracellular release of drugs. A synergistic antitumor efficacy is achieved using hybrid micelles, which release both doxorubicin and α-tocopheryl succinate to display toxicities in the nucleus and mitochondria, respectively.

• Authors: Songzhi Xie, Maohua Chen, Xiaojie Song, Zhao Zhang, Zhanlin Zhang, Zhoujiang Chen, Xiaohong Li
• Journal: Acta biomaterialia (Acta Biomater) Vol. 78 Pg. 198-210 (09 15 2018) ISSN: 1878-7568 [Electronic] England
• PMID: 30036720 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Acids
• Antineoplastic Agents
• Micelles

Topics

• Acids (chemistry)
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Drug Synergism
• Escherichia coli (metabolism)
• Female
• Humans
• Hydrogen-Ion Concentration
• Mice, Inbred BALB C
• Micelles
• Neoplasms (pathology)
• Tissue Distribution