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.
journal_name
Acta Biomaterjournal_title
Acta biomaterialiaauthors
Xie S,Chen M,Song X,Zhang Z,Zhang Z,Chen Z,Li Xdoi
10.1016/j.actbio.2018.07.041subject
Has Abstractpub_date
2018-09-15 00:00:00pages
198-210eissn
1742-7061issn
1878-7568pii
S1742-7061(18)30442-2journal_volume
78pub_type
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pub_type: 杂志文章
doi:10.1016/j.actbio.2017.09.003
更新日期:2017-11-01 00:00:00
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journal_title:Acta biomaterialia
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