Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.
Key Laboratory of Advanced Technologies of Materials, Ministry of Education, School of Materials Science and Engineering, Southwest Jiaotong University, Chengdu 610031, PR China.
Acta Biomater. 2018 Sep 15;78:198-210. doi: 10.1016/j.actbio.2018.07.041. Epub 2018 Jul 21.
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 (PM and PM). Tetrazine and norbornene terminals are grafted on EcN and PM/PM 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 PM/PM 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 (M). The self-assembled micelles from PM/PM with a ratio of 1:2 demonstrate the most significant synergistic efficacy, and the released M 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 M 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.
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.
细菌具有自主导航和特异性渗透入实体瘤的固有特性。在本研究中，我们研究了一种新型细菌微机器人用于传递混合胶束以促进协同抗肿瘤疗效。大肠杆菌 Nissle 1917（EcN）被用作细菌载体，通过酸不稳定的 2-丙稀酸-3-甲基马来酸酐（CDM）连接物固定两亲共聚物。阿霉素（DOX）和 α-生育酚琥珀酸酯（TOS）通过二硫键连接到聚乙二醇上，得到两亲性前胶束聚合物（PM 和 PM）。四嗪和降冰片烯末端分别接枝在 EcN 和 PM/PM 共聚物上，温和的、位点特异性的生物正交反应保持了共轭 EcN 的活力、运动能力和肿瘤积累能力。PM/PM 共聚物在响应轻微酸性肿瘤微环境时从细菌微机器人中释放出来，然后原位形成这些共聚物作为混合胶束（M）。PM/PM 以 1:2 的比例自组装成的胶束表现出最显著的协同疗效，释放的 M 混合胶束表现出类似通过溶剂蒸发制备的胶束的细胞摄取效率、谷胱甘肽（GSH）敏感药物释放和细胞毒性。由于细菌的自主推进特性和 EcN 优先积累在肿瘤中的连续过程，原位形成 M 混合胶束和细胞内药物释放，细菌微机器人在动物生存、肿瘤生长和肿瘤细胞凋亡诱导方面表现出显著的抗肿瘤疗效。因此，我们展示了一种构建细菌微机器人的可行策略，用于实现肿瘤积累和按需释放多种治疗剂以实现协同抗肿瘤疗效。
在将纳米颗粒靶向递送至实体瘤和实现癌症化疗中的协同疗效方面仍然存在挑战。在本研究中，我们探索了一类新型细菌微机器人来负载、递送和释放混合胶束。大肠杆菌 Nissle 1917（EcN）被用作细菌载体，通过酸不稳定的连接物固定两亲共聚物，释放的共聚物自组装成胶束。所得细菌微机器人将自主推进的细菌和自组装的两亲性聚合物整合到胶束中，并实现了从细菌微机器人中响应 pH 释放前胶束聚合物和响应谷胱甘肽释放药物的细胞内释放。通过混合胶束实现了协同抗肿瘤疗效，混合胶束释放阿霉素和 α-生育酚琥珀酸酯分别在核和线粒体中显示毒性。
