Ferroptosis is a form of programmed cell death characterized by overwhelmed lipid oxidation,and it has emerged as a promising strategy for cancer therapy.Enhanced ferroptosis could overcome the limitations of conventi...Ferroptosis is a form of programmed cell death characterized by overwhelmed lipid oxidation,and it has emerged as a promising strategy for cancer therapy.Enhanced ferroptosis could overcome the limitations of conventional therapeutic modalities,particularly in difficult-to-treat tumors.In this study,we developed a dual-modality therapy in nanomedicine by combining paclitaxel(PTX)chemotherapy and pyropheophorbide-a(Ppa)phototherapy.Heparin(HP)was grafted with poly(N-(2′-hydroxy)propyl methacrylamide)(pHPMA)using reversible addition–fragmentation chain transfer polymerization to form HP-pHPMA(HH),which was utilized to deliver Ppa and PTX,yielding HP-pHPMA-Ppa(HH-Ppa)and HP-pHPMA-PTX(HH-PTX),respectively.The prodrug-based combinational nanomedicine(HH-PP)was formed by co-assembly of HH-PTX and HH-Ppa.It was found that HH-PP treatment significantly disrupted lipid metabolism in triple-negative breast cancer(TNBC)cells,induced extensive lipid oxidation,and promoted ferroptosis.In vivo,HH-PP intervention achieved a tumor growth inhibition rate of 86.63%and activated adaptive immunity with an elevated CD8^(+) cytotoxic T cell infiltration level.This combinational nanomedicine offers a promising platform for co-delivery of multiple therapeutic agents.It exerts a promising anti-tumor effect via enhanced ferroptosis and ferroptosis-induced immune activation by disrupting lipid metabolism in TNBC cancer cells.展开更多
The tumor microenvironment-sensitive prodrug-based nanoparticles(NPs)have emerged as a promising drug delivery system(DDS).The shape of these particles plays a crucial role in their in vivo behavior.However,non-spheri...The tumor microenvironment-sensitive prodrug-based nanoparticles(NPs)have emerged as a promising drug delivery system(DDS).The shape of these particles plays a crucial role in their in vivo behavior.However,non-spherical organic NPs are rarely reported due to the inherent flexibility and variability of organic molecules.Herein,we fabricate reduction-sensitive prodrug NPs and explore the impact of their morphology properties on their in vivo fate.Prodrugs are self-assembled into spherical NPs with distearoyl phosphoethanolamine-PEG2000(DSPE-PEG2k),or into rod-shaped NPs with D-a-tocopherol polyethylene glycol 2000 succinate(TPGS2k)due to the stronger binding energy.In comparison with spherical NPs,the endocytosis of rod-shaped NPs predominantly relies on caveolae-mediated pathways rather than clathrin-mediated ones,potentially avoiding degradation by lysosomes.Additionally,the rod-shaped NPs exhibit prolonged circulation time,increased tumor accumulation,and enhanced antitumor ability.Our current findings reveal the significant effect of particle shape on the behavior of prodrug NPs and introduce a novel paradigm for high-efficacy cancer therapy of prodrug NPs.展开更多
Prodrug-based nanoassemblies have emerged as advanced carrier-free nanomedicines.These prodrugs typically consist of drug modules,response modules,and modification modules.The general role of modification modules is t...Prodrug-based nanoassemblies have emerged as advanced carrier-free nanomedicines.These prodrugs typically consist of drug modules,response modules,and modification modules.The general role of modification modules is to modulate the self-assembly ability of the prodrugs.How to optimize the structure of modification modules for balanced efficacy and safety of high-toxicity chemotherapeutic drugs deserves to be further investigated.In this study,a modification strategy of aliphatic alcohols with various chain lengths(SC_(4),SC_(8),SC_(12),SC_(16) and SC_(20))was carried out to design five cabazitaxel(CBZ)prodrugs.Among them,CBZ-SC NPs with shorter chain length(SC_(4) and SC_(8))showed poor self-assembly stability.CBZ-SC_(12) NPs also failed to remain stable while the other two CBZ-SC NPs exhibited good stability.In turn,the drug release rate was hindered by the increasing chain length.CBZ-SC12 NPs caused kidney damage due to their high redox-sensitivity and rapid release rate during circulation.By contrast,CBZ-SC NPs with longer chain length(SC_(16) and SC_(20))not only demonstrated superior stability with improved pharmacokinetic behavior,but also might solve the dilemma of dose-related toxicity caused by CBZ.Overall,these findings emphasized the importance of chain length in modification module to modulate the efficacy and safety of CBZ prodrug nanoassemblies.展开更多
A commercial albumin-bound paclitaxel nano-formulation has been considered a gold standard against breast cancer.However,its application still restricted unfavorable pharmacokinetics and the immunogenicity of exogenou...A commercial albumin-bound paclitaxel nano-formulation has been considered a gold standard against breast cancer.However,its application still restricted unfavorable pharmacokinetics and the immunogenicity of exogenous albumin carrier.Herein,we report an albumin-bound tumor redoxresponsive paclitaxel prodrugs nano-delivery strategy.Using diverse linkages(thioether bond and disulfide bond),paclitaxel(PTX)was conjugated with an albumin-binding maleimide(MAL)functional group.These pure PTX prodrugs could self-assemble to form uniform and spherical nanoparticles(NPs)in aqueous solution without any excipients.By immediately binding to blood circulating albumin after intravenous administration,NPs are rapidly disintegrated into small prodrug/albumin nanoaggregates in vivo,facilitating PTX prodrugs accumulation in the tumor region via albumin receptormediated active targeting.The tumor redox dual-responsive drug release property of prodrugs improves the selectivity of cytotoxicity between normal and cancer cells.Moreover,disulfide bond-containing prodrug/albumin nanoaggregates exhibit long circulation time and superior antitumor efficacy in vivo.This simple and facile strategy integrates the biomimetic characteristic of albumin,tumor redox-responsive on-demand drug release,and provides new opportunities for the development of the high-efficiency antitumor nanomedicines.展开更多
基金supported by the National Key Research and Development Program of China(2023ZD0502304,2023YFB3810004,2022YFC2009900)Natural Science Foundation of China(32271445,52073193)+2 种基金Department of Science and Technology of Sichuan Province(2024NSFJQ0050,China)National Guidance Fund on Developing Local Science and Technology for Sichuan Province(2023ZYD0167,China)1‧3‧5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYGD23026,China).
文摘Ferroptosis is a form of programmed cell death characterized by overwhelmed lipid oxidation,and it has emerged as a promising strategy for cancer therapy.Enhanced ferroptosis could overcome the limitations of conventional therapeutic modalities,particularly in difficult-to-treat tumors.In this study,we developed a dual-modality therapy in nanomedicine by combining paclitaxel(PTX)chemotherapy and pyropheophorbide-a(Ppa)phototherapy.Heparin(HP)was grafted with poly(N-(2′-hydroxy)propyl methacrylamide)(pHPMA)using reversible addition–fragmentation chain transfer polymerization to form HP-pHPMA(HH),which was utilized to deliver Ppa and PTX,yielding HP-pHPMA-Ppa(HH-Ppa)and HP-pHPMA-PTX(HH-PTX),respectively.The prodrug-based combinational nanomedicine(HH-PP)was formed by co-assembly of HH-PTX and HH-Ppa.It was found that HH-PP treatment significantly disrupted lipid metabolism in triple-negative breast cancer(TNBC)cells,induced extensive lipid oxidation,and promoted ferroptosis.In vivo,HH-PP intervention achieved a tumor growth inhibition rate of 86.63%and activated adaptive immunity with an elevated CD8^(+) cytotoxic T cell infiltration level.This combinational nanomedicine offers a promising platform for co-delivery of multiple therapeutic agents.It exerts a promising anti-tumor effect via enhanced ferroptosis and ferroptosis-induced immune activation by disrupting lipid metabolism in TNBC cancer cells.
基金This research was supported by National Natural Science Foundation of China(Nos.82273874 and 82404561)Liaoning Revitalization Talents Program(No.XLYC22202019)+4 种基金the China National Postdoctoral Program for Innovative Talents(No.BX20240233)the Postdoctoral Fellowship Program(Grade B)of China Postdoctoral Science Foundation(No.GZB20240179)the China Postdoctoral Science Foundation(No.2023MD744230)Doctoral Scientific Research Launching Fund Project of Liaoning province(No.2024-BS-075)Prospective Basic research project of 2024 Scientific Research Project of Liaoning Department of Education(No.LJ212410163042).
文摘The tumor microenvironment-sensitive prodrug-based nanoparticles(NPs)have emerged as a promising drug delivery system(DDS).The shape of these particles plays a crucial role in their in vivo behavior.However,non-spherical organic NPs are rarely reported due to the inherent flexibility and variability of organic molecules.Herein,we fabricate reduction-sensitive prodrug NPs and explore the impact of their morphology properties on their in vivo fate.Prodrugs are self-assembled into spherical NPs with distearoyl phosphoethanolamine-PEG2000(DSPE-PEG2k),or into rod-shaped NPs with D-a-tocopherol polyethylene glycol 2000 succinate(TPGS2k)due to the stronger binding energy.In comparison with spherical NPs,the endocytosis of rod-shaped NPs predominantly relies on caveolae-mediated pathways rather than clathrin-mediated ones,potentially avoiding degradation by lysosomes.Additionally,the rod-shaped NPs exhibit prolonged circulation time,increased tumor accumulation,and enhanced antitumor ability.Our current findings reveal the significant effect of particle shape on the behavior of prodrug NPs and introduce a novel paradigm for high-efficacy cancer therapy of prodrug NPs.
基金support from the Key research and development program of Liaoning Province(No.2024JH2/102500061)Youth innovation team of Liaoning Province Department of Education(No.LJ222410163049)Liaoning Revitalization Talents Program(No.XLYC2203083).
文摘Prodrug-based nanoassemblies have emerged as advanced carrier-free nanomedicines.These prodrugs typically consist of drug modules,response modules,and modification modules.The general role of modification modules is to modulate the self-assembly ability of the prodrugs.How to optimize the structure of modification modules for balanced efficacy and safety of high-toxicity chemotherapeutic drugs deserves to be further investigated.In this study,a modification strategy of aliphatic alcohols with various chain lengths(SC_(4),SC_(8),SC_(12),SC_(16) and SC_(20))was carried out to design five cabazitaxel(CBZ)prodrugs.Among them,CBZ-SC NPs with shorter chain length(SC_(4) and SC_(8))showed poor self-assembly stability.CBZ-SC_(12) NPs also failed to remain stable while the other two CBZ-SC NPs exhibited good stability.In turn,the drug release rate was hindered by the increasing chain length.CBZ-SC12 NPs caused kidney damage due to their high redox-sensitivity and rapid release rate during circulation.By contrast,CBZ-SC NPs with longer chain length(SC_(16) and SC_(20))not only demonstrated superior stability with improved pharmacokinetic behavior,but also might solve the dilemma of dose-related toxicity caused by CBZ.Overall,these findings emphasized the importance of chain length in modification module to modulate the efficacy and safety of CBZ prodrug nanoassemblies.
基金supported by National Natural Science Foundation of China(No.81773656 and U1608283)Liaoning Revitalization Talents Program(No XLYC1808017,China)+2 种基金Key projects of Technology bureau in Shenyang(No.18400408,China)Key projects of Liaoning Province Department of Education(No.2017LZD03,China)111 Project(D20029,China)
文摘A commercial albumin-bound paclitaxel nano-formulation has been considered a gold standard against breast cancer.However,its application still restricted unfavorable pharmacokinetics and the immunogenicity of exogenous albumin carrier.Herein,we report an albumin-bound tumor redoxresponsive paclitaxel prodrugs nano-delivery strategy.Using diverse linkages(thioether bond and disulfide bond),paclitaxel(PTX)was conjugated with an albumin-binding maleimide(MAL)functional group.These pure PTX prodrugs could self-assemble to form uniform and spherical nanoparticles(NPs)in aqueous solution without any excipients.By immediately binding to blood circulating albumin after intravenous administration,NPs are rapidly disintegrated into small prodrug/albumin nanoaggregates in vivo,facilitating PTX prodrugs accumulation in the tumor region via albumin receptormediated active targeting.The tumor redox dual-responsive drug release property of prodrugs improves the selectivity of cytotoxicity between normal and cancer cells.Moreover,disulfide bond-containing prodrug/albumin nanoaggregates exhibit long circulation time and superior antitumor efficacy in vivo.This simple and facile strategy integrates the biomimetic characteristic of albumin,tumor redox-responsive on-demand drug release,and provides new opportunities for the development of the high-efficiency antitumor nanomedicines.
