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 intr...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 chemo-sensitization.Bacteria selectively colonized into hypoxic tumor region and modulated tumor microenvironment,including macrophages repolarization and neutrophils infiltration.Specifically,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 effect.Moreover,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 mice.In 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 compatibility.This work provides an efficient trans-BBB/BTB drug delivery strategy via cell hitchhiking for enhanced glioma therapy.展开更多
Protein phosphatases play essential roles as negative regulators of kinases and signaling cascades involved in cytoskeletal organization.Protein phosphatase 2A(PP2A)is highly conserved and is the predominant serine/th...Protein phosphatases play essential roles as negative regulators of kinases and signaling cascades involved in cytoskeletal organization.Protein phosphatase 2A(PP2A)is highly conserved and is the predominant serine/threonine phosphatase in the nervous system,constituting more than 70%of all neuronal phosphatases.PP2A is involved in diverse regulatory functions,including cell cycle progression,apoptosis,and DNA repair.Although PP2A has historically been identified as a tumor suppressor,inhibition of PP2A has paradoxically demonstrated potential as a therapeutic target for various cancers.LB100,a water-soluble,small-molecule competitive inhibitor of PP2A,has shown particular promise as a chemo-and radio-sensitizing agent.Preclinical success has led to a profusion of clinical trials on LB100 adjuvant therapies,including a phase I trial in extensive-stage small-cell lung cancer,a phase I/II trial in myelodysplastic syndrome,a phase II trial in recurrent glioblastoma,and a completed phase I trial assessing the safety of LB100 and docetaxel in various relapsed solid tumors.Herein,we review the development of LB100,the role of PP2A in cancer biology,and recent advances in targeting PP2A inhibition in immunotherapy.展开更多
基金supported by the National Natural Science Foundation of China(Nos.U1903125,82071986,82073799,and 81771827)Natural Science Foundation of Hunan province in China(2021JJ20084)+2 种基金the Science and Technology Project of Hunan Province(2021RC4017 and 2021RC3020,China)the Furong Scholars Programme of Hunan Provincethe Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University(China)。
文摘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 chemo-sensitization.Bacteria selectively colonized into hypoxic tumor region and modulated tumor microenvironment,including macrophages repolarization and neutrophils infiltration.Specifically,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 effect.Moreover,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 mice.In 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 compatibility.This work provides an efficient trans-BBB/BTB drug delivery strategy via cell hitchhiking for enhanced glioma therapy.
基金the NIH Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and contributions to the Foundation for the NIH from the Doris Duke Charitable Foundationthe American Association for Dental Research+2 种基金the Colgate-Palmolive Companyprivate donorssupported partly by the Intramural Research Program at the National Cancer Institute at the NIH
文摘Protein phosphatases play essential roles as negative regulators of kinases and signaling cascades involved in cytoskeletal organization.Protein phosphatase 2A(PP2A)is highly conserved and is the predominant serine/threonine phosphatase in the nervous system,constituting more than 70%of all neuronal phosphatases.PP2A is involved in diverse regulatory functions,including cell cycle progression,apoptosis,and DNA repair.Although PP2A has historically been identified as a tumor suppressor,inhibition of PP2A has paradoxically demonstrated potential as a therapeutic target for various cancers.LB100,a water-soluble,small-molecule competitive inhibitor of PP2A,has shown particular promise as a chemo-and radio-sensitizing agent.Preclinical success has led to a profusion of clinical trials on LB100 adjuvant therapies,including a phase I trial in extensive-stage small-cell lung cancer,a phase I/II trial in myelodysplastic syndrome,a phase II trial in recurrent glioblastoma,and a completed phase I trial assessing the safety of LB100 and docetaxel in various relapsed solid tumors.Herein,we review the development of LB100,the role of PP2A in cancer biology,and recent advances in targeting PP2A inhibition in immunotherapy.
