Stimuli-responsive delivery systems hold promise in cancer treatments.However,their application potential has been limited due to undesirable drug leaking during blood circulation and inefficient therapeutic efficacy ...Stimuli-responsive delivery systems hold promise in cancer treatments.However,their application potential has been limited due to undesirable drug leaking during blood circulation and inefficient therapeutic efficacy in tumors,resulting in undesirable therapeutic outcomes.Herein,we have developed a novel redox-sensitive pegylated phospholipid,termed as DOPE-SS-PEG,which can form a glutathione(GSH)-triggered precision explosive system(GPS)for simultaneously improving circulation stability,tumor specificity,and chemosensitivity,leading to explosive anticancer effects.GPS is constructed of liposomal doxorubicin(DOX)functionalized with DOPE-SS-PEG and MnO_(2) nanoparticles,which can protect liposome structure in the presence of serum GSH(20μM),whereas converts to cationic liposome in response to intracellular GSH(10 mM),thereby enhancing circulation stability,tumor specificity,endosomal escape,and cytoplasmic delivery.Importantly,GPS can not only generate oxygen to relieve hypoxia and consequently enhance chemosensitivity,but quench GSH antioxidability to elevate the accruement of intracellular reactive oxygen species(ROS),leading to an explosion of oxidative stress induced cell injury.Particularly,in vivo studies show that GPS selectively accumulates in tumor tissues,effectively inhibits tumor growth,exhibits minimal systemic adverse effects,and consequently prolongs the survival time of tumor-bearing mice.Therefore,GPS is a unique stimuli-responsive treatment with programmed and on-demand drug delivery,as well as explosive therapeutic efficacy,and provides an intelligent anticancer treatment.展开更多
Cisplatin is a widely applied therapeutics for the treatment of osteosarcoma.However,its clinical applications have been hindered due to low efficacy and bioavailability,and particularly frequent emergence of reactive...Cisplatin is a widely applied therapeutics for the treatment of osteosarcoma.However,its clinical applications have been hindered due to low efficacy and bioavailability,and particularly frequent emergence of reactive oxygen species(ROS)-decrease induced drug resistance.The transcription factor NF-E2-related factor 2(Nrf2)is increased in cancer patients and induces poor outcome in osteosarcoma treatment,making it a novel target to improve the efficacy of chemotherapy.Herein,a hyaluronidase-responsive multi-layer liposome(HLCN)for co-delivery of cisplatin and Nrf2 siRNA(siNrf2)is developed.It is composed of Vpr52-96 modified liposome covered with hyaluronic acid(HA).HLCN selectively accumulates in osteosarcoma by targeting tumor-specific CD44,and can be degraded by endosomal hyaluronidase to generate cationic liposome,which promotes the endosomal escape of Vpr52-96,cisplatin and siNrf2.HLCN can effectively decrease Nrf2 level,promote ROS generation,activate itochondrial apoptotic pathway,and consequently enhance anticancer efficacy of cisplatin.Particularly,HLCN shows high cytotoxicity to osteosarcoma cells with an IC50 value of about 1µM,which is four-fold lower than liposomal cisplatin(IC504µM),indicating that Nrf2 silence can significantly improve cisplatin sensitivity in cancer cells.Importantly,HLCN can remarkably inhibit tumor growth in the xenograft osteosarcoma mice with minimal systemic adverse effects.Therefore,this novel stimuli-responsive combination therapy of cisplatin and siNrf2 provides a promising strategy for the treatment of osteosarcoma.展开更多
基金This work were supported by the National Key Research and Development Program of China(No.2019YFA0802800)the National Key Research and Development Program of China(No.2018YFB1105400)+3 种基金the National Natural Science Foundation of China(No.21472090)the Natural Science Foundation of Jiangsu Province(No.BK20180334)the Fundamental Research Funds for Central Universities Nanjing University,the Scientific Research Foundation of Graduate School of Nanjing University(No.2018CL12)The Key Research and Development Program of Jiangsu Provincial Department of Science and Technology of China(No.BE2019002).
文摘Stimuli-responsive delivery systems hold promise in cancer treatments.However,their application potential has been limited due to undesirable drug leaking during blood circulation and inefficient therapeutic efficacy in tumors,resulting in undesirable therapeutic outcomes.Herein,we have developed a novel redox-sensitive pegylated phospholipid,termed as DOPE-SS-PEG,which can form a glutathione(GSH)-triggered precision explosive system(GPS)for simultaneously improving circulation stability,tumor specificity,and chemosensitivity,leading to explosive anticancer effects.GPS is constructed of liposomal doxorubicin(DOX)functionalized with DOPE-SS-PEG and MnO_(2) nanoparticles,which can protect liposome structure in the presence of serum GSH(20μM),whereas converts to cationic liposome in response to intracellular GSH(10 mM),thereby enhancing circulation stability,tumor specificity,endosomal escape,and cytoplasmic delivery.Importantly,GPS can not only generate oxygen to relieve hypoxia and consequently enhance chemosensitivity,but quench GSH antioxidability to elevate the accruement of intracellular reactive oxygen species(ROS),leading to an explosion of oxidative stress induced cell injury.Particularly,in vivo studies show that GPS selectively accumulates in tumor tissues,effectively inhibits tumor growth,exhibits minimal systemic adverse effects,and consequently prolongs the survival time of tumor-bearing mice.Therefore,GPS is a unique stimuli-responsive treatment with programmed and on-demand drug delivery,as well as explosive therapeutic efficacy,and provides an intelligent anticancer treatment.
基金This work was supported by the National Key Research and Development Program of China(No.2019YFA0802800)the Key Research and Development Program of Jiangsu Provincial Department of Science and Technology of China(No.BE2019002)+5 种基金the Medical Key Young Talents Programs of Jiangsu Province(No.QNRC2016915)the“The Six Top Talents”of Jiangsu Province(No.WSW-112)the Fundamental Research Funds for the Central Universities(No.021314380120)the National Key Research and Development Program of China(No.2018YFB1105400)National Natural Science Foundation of China(No.21708019)Natural Science Foundation of Jiangsu(No.BK20170987).
文摘Cisplatin is a widely applied therapeutics for the treatment of osteosarcoma.However,its clinical applications have been hindered due to low efficacy and bioavailability,and particularly frequent emergence of reactive oxygen species(ROS)-decrease induced drug resistance.The transcription factor NF-E2-related factor 2(Nrf2)is increased in cancer patients and induces poor outcome in osteosarcoma treatment,making it a novel target to improve the efficacy of chemotherapy.Herein,a hyaluronidase-responsive multi-layer liposome(HLCN)for co-delivery of cisplatin and Nrf2 siRNA(siNrf2)is developed.It is composed of Vpr52-96 modified liposome covered with hyaluronic acid(HA).HLCN selectively accumulates in osteosarcoma by targeting tumor-specific CD44,and can be degraded by endosomal hyaluronidase to generate cationic liposome,which promotes the endosomal escape of Vpr52-96,cisplatin and siNrf2.HLCN can effectively decrease Nrf2 level,promote ROS generation,activate itochondrial apoptotic pathway,and consequently enhance anticancer efficacy of cisplatin.Particularly,HLCN shows high cytotoxicity to osteosarcoma cells with an IC50 value of about 1µM,which is four-fold lower than liposomal cisplatin(IC504µM),indicating that Nrf2 silence can significantly improve cisplatin sensitivity in cancer cells.Importantly,HLCN can remarkably inhibit tumor growth in the xenograft osteosarcoma mice with minimal systemic adverse effects.Therefore,this novel stimuli-responsive combination therapy of cisplatin and siNrf2 provides a promising strategy for the treatment of osteosarcoma.
