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
Effective tumor treatment depends on optimizing drug penetration and accumulation in tumor tissue while minimizing systemic toxicity.Nanomedicine has emerged as a key solution that addresses the rapid clearance of fre...Effective tumor treatment depends on optimizing drug penetration and accumulation in tumor tissue while minimizing systemic toxicity.Nanomedicine has emerged as a key solution that addresses the rapid clearance of free drugs,but achieving deep drug penetration into solid tumors remains elusive.This review discusses various strategies to enhance drug penetration,including manipulation of the tumor microenvironment,exploitation of both external and internal stimuli,pioneering nanocarrier surface engineering,and development of innovative tactics for active tumor penetration.One outstanding strategy is organelle-affinitive transfer,which exploits the unique properties of specific tumor cell organelles and heralds a potentially transformative approach to active transcellular transfer for deep tumor penetration.Rigorous models are essential to evaluate the efficacy of these strategies.The patient-derived xenograft(PDX)model is gaining traction as a bridge between laboratory discovery and clinical application.However,the journey from bench to bedside for nanomedicines is fraught with challenges.Future efforts should prioritize deepening our understanding of nanoparticle-tumor interactions,re-evaluating the EPR effect,and exploring novel nanoparticle transport mechanisms.展开更多
Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells.Herein,we constructed a PEGylated dendritic ep...Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells.Herein,we constructed a PEGylated dendritic epirubicin(Epi)prodrug(Epi-P4D)to regulate the metabolism of cancer-associated fibroblasts(CAFs),thus enhancing Epi penetration into both multicellular tumor spheroids(MTSs)and tumor tissues in mouse colon cancer(CT26),mouse breast cancer(4T1)and human breast cancer(MDA-MB-231)models.Enhanced cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin,α-SMA,and collagen secretion.Besides,thinning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell(DC)maturation and subsequent immune activation,including elevating the CD4^(+)T cell population,reducing CD4^(+)and CD8^(+)T cell hyperactivation and exhaustion,and amplifying the natural killer(NK)cell proportion and effectively activating them.As a result,this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy.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financially supported by the National Natural Science Foundation of China(32271445,52073193,32271382)National Key Research and Development Program of China(2022YFC2009900)1·3·5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYJC21013).
文摘Effective tumor treatment depends on optimizing drug penetration and accumulation in tumor tissue while minimizing systemic toxicity.Nanomedicine has emerged as a key solution that addresses the rapid clearance of free drugs,but achieving deep drug penetration into solid tumors remains elusive.This review discusses various strategies to enhance drug penetration,including manipulation of the tumor microenvironment,exploitation of both external and internal stimuli,pioneering nanocarrier surface engineering,and development of innovative tactics for active tumor penetration.One outstanding strategy is organelle-affinitive transfer,which exploits the unique properties of specific tumor cell organelles and heralds a potentially transformative approach to active transcellular transfer for deep tumor penetration.Rigorous models are essential to evaluate the efficacy of these strategies.The patient-derived xenograft(PDX)model is gaining traction as a bridge between laboratory discovery and clinical application.However,the journey from bench to bedside for nanomedicines is fraught with challenges.Future efforts should prioritize deepening our understanding of nanoparticle-tumor interactions,re-evaluating the EPR effect,and exploring novel nanoparticle transport mechanisms.
基金supported by the National Science and Technology Major Project of China(2023YFB3810004)the National Natural Science Foundation of China(32271445,52103175,32271382,32101145)+4 种基金the National Key Research and Development Program of China(2022YFC2009900)Department of Science and Technology of Sichuan Province(24NSFJQ0167,China)1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC21013,China)Post-Doctor Research Project,West China Hospital,Sichuan University(2021HXBH055,2021HXBH057,China)China Postdoctoral Science Foundation(2021M692314).
文摘Inefficient drug penetration hurdled by the stroma in the tumor tissue leads to a diminished therapeutic effect for drugs and a reduced infiltration level of immune cells.Herein,we constructed a PEGylated dendritic epirubicin(Epi)prodrug(Epi-P4D)to regulate the metabolism of cancer-associated fibroblasts(CAFs),thus enhancing Epi penetration into both multicellular tumor spheroids(MTSs)and tumor tissues in mouse colon cancer(CT26),mouse breast cancer(4T1)and human breast cancer(MDA-MB-231)models.Enhanced cytotoxicity against CT26 MTSs and remarkable antitumor efficacy of Epi-P4D were ascribed to reduced fibronectin,α-SMA,and collagen secretion.Besides,thinning of the tumor tissue stroma and efficient eradication of tumor cells promoted the immunogenic cell death effect for dendritic cell(DC)maturation and subsequent immune activation,including elevating the CD4^(+)T cell population,reducing CD4^(+)and CD8^(+)T cell hyperactivation and exhaustion,and amplifying the natural killer(NK)cell proportion and effectively activating them.As a result,this dendritic nanomedicine thinned the stroma of tumor tissues to enhance drug penetration and facilitate immune cell infiltration for elevated antitumor efficacy.
