To improve the therapeutic effect of rhaponticin （RHA）, a folate receptor （FR） targeted RHA prodrug was designed and regioselectively synthesized by utilizing a hydrophilic peptide spacer linked to folic acid （FA...To improve the therapeutic effect of rhaponticin （RHA）, a folate receptor （FR） targeted RHA prodrug was designed and regioselectively synthesized by utilizing a hydrophilic peptide spacer linked to folic acid （FA） via a releasable disulfide linker. A series of biological evaluation was investigated in vitro and in vivo. The positive results of biological investigations warrant further preclinical study before this novel targeted chemotherapeutic is considered for clinical investigation.展开更多
Bone tumor is a refractory neoplastic growth of tissue in bone. According to the unique environment and phys-chemical characteristics of bone tissues, the chemotherapeutic agents are unlikely to prolong the survival o...Bone tumor is a refractory neoplastic growth of tissue in bone. According to the unique environment and phys-chemical characteristics of bone tissues, the chemotherapeutic agents are unlikely to prolong the survival of patients and often associated with systemic side effects. The bone targeting drug delivery via systemic administration may provide both better treatment efficacy and less frequent administration. In this study, we describe the synthesis, in vitro and in vivo evaluation of novel melphalan-bisphosphonate hybrids, with a tumor microenvironment sensitive linkage, which could be enzymatic activation under tumor microenvironment conditions. We have also evaluated the in vitro targeting efficiency of these prodrugs via the affinity of hydroxyapatite （HA） and cellular proliferation. The in vivo distribution suggested the bisphosphonate conjugated prodrugs with high bone selectivity.展开更多
Kidney-targeted drug delivery systems represent a promising technology to improve drug efficacy and safety in the treatment of renal diseases.In this review,we summarize the strategies that have been employed to devel...Kidney-targeted drug delivery systems represent a promising technology to improve drug efficacy and safety in the treatment of renal diseases.In this review,we summarize the strategies that have been employed to develop kidney-targeted drug delivery systems.We also describe how macromolecular carriers and prodrugs play crucial roles in targeting drugs to particular target cells in the kidney.New technologies render it possible to create renal targeting conjugates and other delivery systems including nanoparticles and liposomes present promising strategies to achieve the goal of targeting drugs to the kidney.展开更多
Ac-Phe-Lys-PABC-DOX（PDOX） is a smart doxorubicin（DOX） prodrug designed to decrease toxicities while maintaining the potent anticancer effects of DOX. This study was aimed at elucidating the effectiveness and toxic...Ac-Phe-Lys-PABC-DOX（PDOX） is a smart doxorubicin（DOX） prodrug designed to decrease toxicities while maintaining the potent anticancer effects of DOX. This study was aimed at elucidating the effectiveness and toxicities of DOX and PDOX in patient-derived MCF-7 breast cancer cells in vitro. The MCF-7 cells were exposed to both PDOX and DOX, and cytotoxicities, cell cycle and P53/P21 signaling alterations were studied. Abundant cathepsin B was found in the MCF-7 cells, and treatment with PDOX and DOX triggered dose- and time-dependent cytotoxicity and resulted in a significant reduction in cell viability. The IC50 of PDOX and DOX was 3.91 and 0.94 μmol/L, respectively. Both PDOX and DOX caused an up-regulation of the P53/P21-related signal pathway, and PDOX significantly increased expression of P53 and caspase 3, and arrested the cell cycle at the G1/G2 phase. As compared with DOX, PDOX reduced toxicities, and it may have different action mechanisms on breast cancer cells.展开更多
Targeted prodrug strategy,which utilizes the endogenous biomarkers in cancer cells as activators to release the active drug,has been well established either in the fundamental research or the clinical treatment.Howeve...Targeted prodrug strategy,which utilizes the endogenous biomarkers in cancer cells as activators to release the active drug,has been well established either in the fundamental research or the clinical treatment.However,many prodrugs suffer from safety concern due to“off-target activation”.Dual or multiple biomarkers triggered prodrug may provide an effective strategy to overcoming the“off-target effect”.Melanoma cells have both high levels of reactive oxygen species(ROS)and tyrosinase(TYR),which makes them significantly different from other tumor cells and normal cells.Here we reported a series of quinazolinone-aryl boronic acid/ester-based prodrugs,which can be activated by the cascade of ROS and TYR and selectively kill melanoma cells.The structure-activity relationship(SAR)analysis revealed that mitochondria-targeting property was vital for their cytotoxicity and the dual activated effector played a significant role in their selectivity towards melanoma cells.Among these candidates,compound 4b showed the highest toxicity to B16,leading to an imbalance of the redox system in melanoma cells,causing mitochondrial DNA damage,and then promoting melanoma cells death.展开更多
基金supported by the National Scientific Foundation of China(No81001622)
文摘To improve the therapeutic effect of rhaponticin （RHA）, a folate receptor （FR） targeted RHA prodrug was designed and regioselectively synthesized by utilizing a hydrophilic peptide spacer linked to folic acid （FA） via a releasable disulfide linker. A series of biological evaluation was investigated in vitro and in vivo. The positive results of biological investigations warrant further preclinical study before this novel targeted chemotherapeutic is considered for clinical investigation.
基金financially supported by the National Natural Science Foundation of China (Nos. 31600811, 81573154, 81773432)the Application Fundamental Research Foundation of Sichuan Province Science and Technology Department, China (Nos. 2016JY0157, 2017JY0123)Scientific Research Foundation of the Health and Family Planning Commission of Sichuan Province, China (Nos. 17PJ556, 17PJ563)
文摘Bone tumor is a refractory neoplastic growth of tissue in bone. According to the unique environment and phys-chemical characteristics of bone tissues, the chemotherapeutic agents are unlikely to prolong the survival of patients and often associated with systemic side effects. The bone targeting drug delivery via systemic administration may provide both better treatment efficacy and less frequent administration. In this study, we describe the synthesis, in vitro and in vivo evaluation of novel melphalan-bisphosphonate hybrids, with a tumor microenvironment sensitive linkage, which could be enzymatic activation under tumor microenvironment conditions. We have also evaluated the in vitro targeting efficiency of these prodrugs via the affinity of hydroxyapatite （HA） and cellular proliferation. The in vivo distribution suggested the bisphosphonate conjugated prodrugs with high bone selectivity.
基金This work was supported by the National Natural Science Foundation(No.81130060)of Chinathe National Science&Technology Major Project of China(No.2011ZX09310-002)。
文摘Kidney-targeted drug delivery systems represent a promising technology to improve drug efficacy and safety in the treatment of renal diseases.In this review,we summarize the strategies that have been employed to develop kidney-targeted drug delivery systems.We also describe how macromolecular carriers and prodrugs play crucial roles in targeting drugs to particular target cells in the kidney.New technologies render it possible to create renal targeting conjugates and other delivery systems including nanoparticles and liposomes present promising strategies to achieve the goal of targeting drugs to the kidney.
基金supported by the grants from the Science Fund for Doctorate Mentors by Ministry of Education of China(No.20120141110042)New Strategies to Treat Peritoneal Carcinomatosis from Hubei Sciences and Technology Bureau,China(No.2008BCC011,and No.2060402-542)the Fundamental Research Fund for the Central Universities of China(No.2012303020208)
文摘Ac-Phe-Lys-PABC-DOX（PDOX） is a smart doxorubicin（DOX） prodrug designed to decrease toxicities while maintaining the potent anticancer effects of DOX. This study was aimed at elucidating the effectiveness and toxicities of DOX and PDOX in patient-derived MCF-7 breast cancer cells in vitro. The MCF-7 cells were exposed to both PDOX and DOX, and cytotoxicities, cell cycle and P53/P21 signaling alterations were studied. Abundant cathepsin B was found in the MCF-7 cells, and treatment with PDOX and DOX triggered dose- and time-dependent cytotoxicity and resulted in a significant reduction in cell viability. The IC50 of PDOX and DOX was 3.91 and 0.94 μmol/L, respectively. Both PDOX and DOX caused an up-regulation of the P53/P21-related signal pathway, and PDOX significantly increased expression of P53 and caspase 3, and arrested the cell cycle at the G1/G2 phase. As compared with DOX, PDOX reduced toxicities, and it may have different action mechanisms on breast cancer cells.
基金supported by the National Natural Science Foundation of China(No.31871365 and 22177029)the Fundamental Research Funds for the Central Universities,China.
文摘Targeted prodrug strategy,which utilizes the endogenous biomarkers in cancer cells as activators to release the active drug,has been well established either in the fundamental research or the clinical treatment.However,many prodrugs suffer from safety concern due to“off-target activation”.Dual or multiple biomarkers triggered prodrug may provide an effective strategy to overcoming the“off-target effect”.Melanoma cells have both high levels of reactive oxygen species(ROS)and tyrosinase(TYR),which makes them significantly different from other tumor cells and normal cells.Here we reported a series of quinazolinone-aryl boronic acid/ester-based prodrugs,which can be activated by the cascade of ROS and TYR and selectively kill melanoma cells.The structure-activity relationship(SAR)analysis revealed that mitochondria-targeting property was vital for their cytotoxicity and the dual activated effector played a significant role in their selectivity towards melanoma cells.Among these candidates,compound 4b showed the highest toxicity to B16,leading to an imbalance of the redox system in melanoma cells,causing mitochondrial DNA damage,and then promoting melanoma cells death.
