Pancreatic cancer is a more aggressive and refractory malignancy.Resistance and toxicity limit drug efficacy.Herein,we report a lower toxic and higher effective miriplatin(MPt)-loaded liposome,LMPt,exhibiting totally ...Pancreatic cancer is a more aggressive and refractory malignancy.Resistance and toxicity limit drug efficacy.Herein,we report a lower toxic and higher effective miriplatin(MPt)-loaded liposome,LMPt,exhibiting totally different anti-cancer mechanism from previously reported platinum agents.Both in gemcitabine(GEM)-resistant/sensitive(GEM-R/S)pancreatic cancer cells,LMPt exhibits prominent anti-cancer activity,led by faster cellular entry-induced larger accumulation of MPt.The level of caveolin-1(Cav-1)determines entry rate and switch of entry pathways of LMPt,indicating a novel role of Cav-1 in nanoparticle entry.After endosome-lysosome processing,in unchanged metabolite,MPt is released and targets mitochondria to enhance binding of mitochondria protease LONP1 with POLG and TFAM,to degrade POLG and TFAM.Then,via PINK1-Parkin axis,mitophagy is induced by POLG and TFAM degradation-initiated mitochondrial DNA(mtDNA)replication blocking.Additionally,POLG and TFAM are identified as novel prognostic markers of pancreatic cancer,and mtDNA replication-induced mitophagy blocking mediates their pro-cancer activity.Our findings reveal that the target of this liposomal platinum agent is mitochondria but not DNA(target of most platinum agents),and totally distinct mechanism of MPt and other formulations of MPt.Self-assembly offers LMPt special efficacy and mechanisms.Prominent action and characteristic mechanism make LMPt a promising cancer candidate.展开更多
Previously developed Asn-Gly-Arg(NGR) peptide-modified multifunctional poly(ethyleneimine)–poly(ethylene glycol)(PEI–PEG)-based nanoparticles(TPIC) have been considered to be promising carriers for the co-delivery o...Previously developed Asn-Gly-Arg(NGR) peptide-modified multifunctional poly(ethyleneimine)–poly(ethylene glycol)(PEI–PEG)-based nanoparticles(TPIC) have been considered to be promising carriers for the co-delivery of DNA and doxorubicin(DOX). As a continued effort, the aim of the present study was to further evaluate the interaction between TPIC and human umbilical vein endothelial cells(HUVEC) to better understand the cellular entry mechanism. In the present investigation,experiments relevant to co-localization, endocytosis inhibitors and factors influencing the internalization were performed. Without any treatment, there was no co-localization between aminopeptidase N/CD13(APN/CD13) and caveolin 1(CAV1). However, co-localization between CD13 and CAV1 was observed when cells were incubated with an anti-CD13 antibody or TPIC. As compared with antibody treatment,TPIC accelerated the speed and enhanced the degree of co-localization. TPIC entered HUVEC not only together with CD13 but also together with CAV1. However, this internalization was not dependent on the enzyme activity of CD13 but could be inhibited by methyl-β-eyclodextfin(MβCD), further identifying the involvement of caveolae-mediated endocytosis(CvME). This conclusion was also verified by endocytosis inhibitor experiments.展开更多
基金supported by grants from CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-2-002,2021-I2M-1030,China)National Natural Science Foundation of China (No.81473249 and 81102464)+2 种基金Drug Innovation Major Project of China (2018ZX09711001-007-002)National Key Research and Development Program of China (2016YFA0201504)National Mega-project for Innovative Drugs (2014ZX09201042,China)。
文摘Pancreatic cancer is a more aggressive and refractory malignancy.Resistance and toxicity limit drug efficacy.Herein,we report a lower toxic and higher effective miriplatin(MPt)-loaded liposome,LMPt,exhibiting totally different anti-cancer mechanism from previously reported platinum agents.Both in gemcitabine(GEM)-resistant/sensitive(GEM-R/S)pancreatic cancer cells,LMPt exhibits prominent anti-cancer activity,led by faster cellular entry-induced larger accumulation of MPt.The level of caveolin-1(Cav-1)determines entry rate and switch of entry pathways of LMPt,indicating a novel role of Cav-1 in nanoparticle entry.After endosome-lysosome processing,in unchanged metabolite,MPt is released and targets mitochondria to enhance binding of mitochondria protease LONP1 with POLG and TFAM,to degrade POLG and TFAM.Then,via PINK1-Parkin axis,mitophagy is induced by POLG and TFAM degradation-initiated mitochondrial DNA(mtDNA)replication blocking.Additionally,POLG and TFAM are identified as novel prognostic markers of pancreatic cancer,and mtDNA replication-induced mitophagy blocking mediates their pro-cancer activity.Our findings reveal that the target of this liposomal platinum agent is mitochondria but not DNA(target of most platinum agents),and totally distinct mechanism of MPt and other formulations of MPt.Self-assembly offers LMPt special efficacy and mechanisms.Prominent action and characteristic mechanism make LMPt a promising cancer candidate.
基金supported by the National Natural Science Foundation(No.81402867)
文摘Previously developed Asn-Gly-Arg(NGR) peptide-modified multifunctional poly(ethyleneimine)–poly(ethylene glycol)(PEI–PEG)-based nanoparticles(TPIC) have been considered to be promising carriers for the co-delivery of DNA and doxorubicin(DOX). As a continued effort, the aim of the present study was to further evaluate the interaction between TPIC and human umbilical vein endothelial cells(HUVEC) to better understand the cellular entry mechanism. In the present investigation,experiments relevant to co-localization, endocytosis inhibitors and factors influencing the internalization were performed. Without any treatment, there was no co-localization between aminopeptidase N/CD13(APN/CD13) and caveolin 1(CAV1). However, co-localization between CD13 and CAV1 was observed when cells were incubated with an anti-CD13 antibody or TPIC. As compared with antibody treatment,TPIC accelerated the speed and enhanced the degree of co-localization. TPIC entered HUVEC not only together with CD13 but also together with CAV1. However, this internalization was not dependent on the enzyme activity of CD13 but could be inhibited by methyl-β-eyclodextfin(MβCD), further identifying the involvement of caveolae-mediated endocytosis(CvME). This conclusion was also verified by endocytosis inhibitor experiments.
