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Salmonella-mediated blood-brain barrier penetration,tumor homing and tumor microenvironment regulation for enhanced chemo/bacterial glioma therapy

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Acta Pharmaceutica Sinica B 2023年第2期13卷 819-833页

作者： Ze Mi Qing Yao Yan Qi Jinhai Zheng Jiahao Liu Zhenguo Liu Hongpei Tan Xiaoqian Ma Wenhu Zhou Pengfei Rong Department of Radiology The Third Xiangya HospitalCentral South UniversityChangsha 410013China Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Department of Pathology Shihezi University School of Medicine and the First Affiliated Hospital to Shihezi University School of MedicineShihezi 832003China Key Laboratory of Biological Nanotechnology of National Health Commission Changsha 410082China School of Biomedical Sciences Hunan UniversityChangsha 410082China Department of Pathology Cangzhou Central Hospital&the Affiliated to Hebei Medical UniversityCangzhou 062650China

Chemotherapy is an important adjuvant treatment of glioma,while the efficacy is far from satisfactory,due not only to the biological barriers of blood-brain barrier(BBB)and blood-tumor barrier(BTB)but also to the intrinsic resistance of glioma cells via multiple survival mechanisms such as upregulation of P-glycoprotein(P-gp).To address these limitations,we report a bacteria-based drug delivery strategy for BBB/BTB transportation,glioma targeting,and *** selectively colonized into hypoxic tumor region and modulated tumor microenvironment,including macrophages repolarization and neutrophils ***,tumor migration of neutrophils was employed as hitchhiking delivery of doxorubicin(DOX)-loaded bacterial outer membrane vesicles(OMVs/DOX).By virtue of the surface pathogen-associated molecular patterns derived from native bacteria,OMVs/DOX could be selectively recognized by neutrophils,thus facilitating glioma targeted delivery of drug with significantly enhanced tumor accumulation by 18-fold as compared to the classical passive targeting ***,the P-gp expression on tumor cells was silenced by bacteria typeⅢsecretion effector to sensitize the efficacy of DOX,resulting in complete tumor eradication with 100%survival of all treated *** addition,the colonized bacteria were finally cleared by anti-bacterial activity of DOX to minimize the potential infection risk,and cardiotoxicity of DOX was also avoided,achieving excellent *** work provides an efficient trans-BBB/BTB drug delivery strategy via cell hitchhiking for enhanced glioma therapy.

关键词： Glioma neutrophil hitchhiking Blood-brain barrier Chemo-sensitization Outer membrane vesicles Doxorubicin P-glycoprotein Salmonella

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