Escherichia coli Nissle 1917-driven microrobots for effective tumor targeted drug delivery and tumor regression.

Potent tumor regression remains challenging due to the lack of effective targeted drug delivery into deep tumors as well as the reduced susceptibility of cancer cells to anticancer agents in hypoxic environments. Bacteria-driven drug-delivery systems are promising carriers in overcoming targeting and diffusion limits that are inaccessible for conventional antitumor drugs. In this study, probiotic facultative anaerobe Escherichia coli Nissle 1917 (EcN) was functionalized and formed self-propelled microrobots to actively deliver therapeutic drug and photosensitizer to the deep hypoxic regions of tumors. Doxorubicin (Dox) was firstly modified with cis-aconityl anhydride (CA) and terminal thiol-decorated hydrazone derivative (Hyd-SH) through dual pH-sensitive amide and imine bonds, respectively. The functionalized CA-Dox-Hyd-SH was further coordinated with photosensitizer gold nanorods (AuNRs) and then conjugated to the surface of EcN. The resulting microrobots (EcN-Dox-Au) inherited the mobility characteristics and bioactivity of native EcN. Upon the irradiation of NIR laser, the microrobots exhibited enhanced tumor accumulation and penetration into the deep hypoxia tumor site. Strikingly, after 21 days of treatment with EcN-Dox-Au formulations, complete tumor regression was achieved without relapse for at least 53 days. This self-propelled strategy utilizing bacteria-driven microrobots provides a promising paradigm for enhancing drug penetration and elevating chemosensitivity, resulting in a superior antitumor effect. STATEMENT OF SIGNIFICANCE: Self-propelled Escherichia coli Nissle 1917 (EcN) - mediated microrobots are functionalized to co-deliver therapeutic drugs and photosensitizers to the deep tumor site. Anti-tumor drug doxorubicin (Dox) was modified through dual pH-sensitive bonds on both terminals and then linked with EcN and photosensitizer gold nanorods (AuNRs) to realize tumor microenvironment acidic pH-responsive drug release. Upon irradiation with a NIR laser near the tumor site, AuNRs produced a photothermal effect which realized the superficial tumor thermal ablation and increased the permeability of the tumor cell membrane to facilitate the penetration of microrobots. Moreover, the deep penetration of microrobots also enhanced the susceptibility of the cancer cells to Dox, and realized the complete tumor regression in the established breast cancer-bearing mice without recurrence using a lower dose of drug regimen.

Gold nanorods-loaded chitosan-based nanomedicine platform enabling an effective tumor regression in vivo.

The clinical utility of 7-ethyl-10-hydroxycamptothecin (SN-38) is hampered by its low water solubility and reduced bioactivity at neutral or alkaline conditions. The rational design of an effective drug delivery system that can significantly enhance the therapeutic index of SN-38 and achieve complete tumor regression still remains a challenge. Herein, chitosan-based hybrid nanoparticles system co-loading with chemotherapeutic drug SN-38 and gold nanorods (AuNRs) was engineered for effective combinational photothermal-chemotherapy. To increase the solubility of SN-38, soluble polymeric prodrug poly (l-glutamic acid)-SN38 (l-PGA-SN38) was firstly synthesized and then complexed with chitosan to form stable nanomedicine via a mild and facile way without using any organic solvent or surfactant. Upon introducing AuNRs into chitosan-based nanomedicine by coordination interaction between the amine group of chitosan and AuNRs, the hybrid nanoparticles exhibited distinct synergistic therapeutic effect compared with single chemotherapy or photothermal treatment in vitro and in vivo. Almost complete tumor regression was achieved after 21-day treatment of the developed hybrid nanoparticles and showed no recurrence for at least 60 days.

Exploring the In Situ Formation Mechanism of Polymeric Aluminum Chloride-Silica Gel Composites under Mechanical Grinding Conditions: As a High-Performance Nanocatalyst for the Synthesis of Xanthene and Pyrimidinone Compounds.

The use of mechanical ball milling to facilitate the synthesis of organic compounds has attracted intense interest from organic chemists. Herein, we report a new process for the preparation of xanthene and pyrimidinone compounds by a one-pot method using polymeric aluminum chloride (PAC), silica gel, and reaction raw materials under mechanical grinding conditions. During the grinding process, polymeric aluminum chloride and silica gel were reconstituted in situ to obtain a new composite catalyst (PAC-silica gel). This catalyst has good stability (six cycles) and wide applicability (22 substrates). The Al-O-Si active center formed by in situ grinding recombination was revealed to be the key to the effective catalytic performance of the PAC-silica gel composites by the comprehensive analysis of the catalytic materials before and after use. In addition, the mechanism of action of the catalyst was verified using density functional theory, and the synthetic pathway of the xanthene compound was reasonably speculated with the experimental data. Mechanical ball milling serves two purposes in this process: not only to induce the self-assembly of silica and PAC into new composites but also to act as a driving force for the catalytic reaction to take place. From a practical point of view, this "one-pot" catalytic method eliminates the need for a complex preparation process for catalytic materials. This is a successful example of the application of mechanochemistry in materials and organic synthesis, offering unlimited possibilities for the application of inorganic polymer materials in green synthesis and catalysis promoted by mechanochemistry.

Probiotic Escherichia coli NISSLE 1917 for inflammatory bowel disease applications.

Escherichia coli NISSLE 1917 (EcN) is a Gram-negative strain with many prominent probiotic properties in the treatment of intestinal diseases such as diarrhea and inflammatory bowel disease (IBD), in particular ulcerative colitis. EcN not only exhibits antagonistic effects on a variety of intestinal pathogenic bacteria, but also regulates the secretion of immune factors in vivo and enhances the ability of host immunity. In this review, the mechanisms of EcN in the remission of inflammatory bowel disease are proposed and recent advances on the functionalized EcN are compiled to provide novel therapeutic strategies for the prevention and treatment of IBD.