Ca^(2+)plays critical roles in the development of diseases,whereas existing various Ca regulation methods have been greatly restricted in their clinical applications due to their high toxicity and inefficiency.To solv...Ca^(2+)plays critical roles in the development of diseases,whereas existing various Ca regulation methods have been greatly restricted in their clinical applications due to their high toxicity and inefficiency.To solve this issue,with the help of Ca overexpressed tumor drug resistance model,the phytic acid(PA)-modified CeO_(2) nano-inhibitors have been rationally designed as an unprecedentedly safe and efficient Ca2+inhibitor to successfully reverse tumor drug resistance through Ca^(2+)negative regulation strategy.Using doxorubicin(Dox)as a model chemotherapeutic drug,the Ca^(2+)nano-inhibitors efficiently deprived intracellular excessive free Ca2+,suppressed P-glycoprotein(P-gp)expression and significantly enhanced intracellular drug accumulation in Dox-resistant tumor cells.This Ca^(2+)negative regulation strategy improved the intratumoral Dox concentration by a factor of 12.4 and nearly eradicated tumors without obvious adverse effects.Besides,nanocerias as pH-regulated nanozyme greatly alleviated the adverse effects of chemotherapeutic drug on normal cells/organs and substantially improved survivals of mice.We anticipate that this safe and effective Ca^(2+)negative regulation strategy has potentials to conquer the pitfalls of traditional Ca inhibitors,improve therapeutic efficacy of common chemotherapeutic drugs and serves as a facile and effective treatment platform of other Ca^(2+) associated diseases.展开更多
Nanoparticle-based chemophotothermal therapy(CPT)is a promising treatment for multidrug resistant tumors.In this study,a drug nanococktail of DIR825@histone was developed by employing doxorubicin(DOX),NIR dye IR825 an...Nanoparticle-based chemophotothermal therapy(CPT)is a promising treatment for multidrug resistant tumors.In this study,a drug nanococktail of DIR825@histone was developed by employing doxorubicin(DOX),NIR dye IR825 and human histones for interventional nucleus-targeted CPT of multidrug resistant tumors with an interventional laser.After localized intervention,DIR825@histone penetrated tumor tissues by transcytosis,efficiently entered tumor cells and targeted the cell nuclei.DIR825@histone also exhibited good photothermal performance and thermal-triggered drug release.Efficient multidrug resistant tumor inhibition was achieved by enhanced CPT sensitization and MDR reversion via nuclear targeting.Moreover,an interventional laser assisted DIR825@histone in inhibiting multidrug resistant tumors by promoting the sufficient delivery of laser energy inside the tumor while reducing skin injury.Therefore,DIR825@histone together with this interventional nucleus-targeted CPT strategy holds great promise for treating multidrug resistant tumors.展开更多
基金This work was financially supported by the National Natural Science Foundation of China(Nos.52002314,21872109,81802841,and 81702999)China Postdoctoral Science Foundation(Nos.2018M633504 and 2018M633749)+3 种基金The study was also supported by the National Natural Science Foundation of Shaanxi Province(No.2019JQ-486)the Natural Science Basic Research Plan in Shaanxi Province(No.2019JM-033)Technology Innovation Development Foundation of Tangdu Hospital(No.2019QYTS003)Authors also acknowledge the support from the Fundamental Research Funds for the Central Universities(Nos.D5000210829 and G2021KY05102).
文摘Ca^(2+)plays critical roles in the development of diseases,whereas existing various Ca regulation methods have been greatly restricted in their clinical applications due to their high toxicity and inefficiency.To solve this issue,with the help of Ca overexpressed tumor drug resistance model,the phytic acid(PA)-modified CeO_(2) nano-inhibitors have been rationally designed as an unprecedentedly safe and efficient Ca2+inhibitor to successfully reverse tumor drug resistance through Ca^(2+)negative regulation strategy.Using doxorubicin(Dox)as a model chemotherapeutic drug,the Ca^(2+)nano-inhibitors efficiently deprived intracellular excessive free Ca2+,suppressed P-glycoprotein(P-gp)expression and significantly enhanced intracellular drug accumulation in Dox-resistant tumor cells.This Ca^(2+)negative regulation strategy improved the intratumoral Dox concentration by a factor of 12.4 and nearly eradicated tumors without obvious adverse effects.Besides,nanocerias as pH-regulated nanozyme greatly alleviated the adverse effects of chemotherapeutic drug on normal cells/organs and substantially improved survivals of mice.We anticipate that this safe and effective Ca^(2+)negative regulation strategy has potentials to conquer the pitfalls of traditional Ca inhibitors,improve therapeutic efficacy of common chemotherapeutic drugs and serves as a facile and effective treatment platform of other Ca^(2+) associated diseases.
基金This work was financially supported by National Natural Science Foundation of China(No.81701822)Heilongjiang Province Science Foundation for Youths(No.QC2018090)+3 种基金the Fundamental Research Funds for Central Universities(No.2572017PZ09)China Postdoctoral Science Foundation(No.2016M600238)Heilongjiang Postdoctoral Special Fund(No.LBH-TZ1601)Northeast Forestry University Double First-Rate Construction Fund(No.000/41113281).
文摘Nanoparticle-based chemophotothermal therapy(CPT)is a promising treatment for multidrug resistant tumors.In this study,a drug nanococktail of DIR825@histone was developed by employing doxorubicin(DOX),NIR dye IR825 and human histones for interventional nucleus-targeted CPT of multidrug resistant tumors with an interventional laser.After localized intervention,DIR825@histone penetrated tumor tissues by transcytosis,efficiently entered tumor cells and targeted the cell nuclei.DIR825@histone also exhibited good photothermal performance and thermal-triggered drug release.Efficient multidrug resistant tumor inhibition was achieved by enhanced CPT sensitization and MDR reversion via nuclear targeting.Moreover,an interventional laser assisted DIR825@histone in inhibiting multidrug resistant tumors by promoting the sufficient delivery of laser energy inside the tumor while reducing skin injury.Therefore,DIR825@histone together with this interventional nucleus-targeted CPT strategy holds great promise for treating multidrug resistant tumors.
