Legumain is a C13 family cysteine protease.It plays diverse roles under both physiological and pathological conditions.The high-level expression of legumain is detected in solid tumors.Legumain promotes the proliferat...Legumain is a C13 family cysteine protease.It plays diverse roles under both physiological and pathological conditions.The high-level expression of legumain is detected in solid tumors.Legumain promotes the proliferation and migration of tumor cells.However,the effect of legumain in blood diseases has not been established.In this report,we studied the effect of legumain on leukemia cells by overexpressing it in THP1 cells.The results demonstrated that legumain promoted cell proliferation,whereas it had little effect on cell apoptosis.Furthermore,legumain promoted the migration of THP1 cells.It was worth noting that legumain decreased the stemness of THP1 cells.Further evidence showed that legumain decreased the expression of Oct4,Sox2,Myc in THP1 cells.Our study reveals the multifaced effects of legumain in leukemia cells and broadens the knowledge of legumain in malignancies.展开更多
Insufficient intratumoral retention of nanomedicines remains the major challenge for broad implementation in clinical sets.Herein,we proposed a legumain-triggered aggregable gold nanoparticle(GNP)delivery platform(GNP...Insufficient intratumoral retention of nanomedicines remains the major challenge for broad implementation in clinical sets.Herein,we proposed a legumain-triggered aggregable gold nanoparticle(GNP)delivery platform(GNPs-A&C).GNPs-A&C could form intratumoral or intracellular aggregates in response to the overexpressed legumain.The aggregates with size increase not only could reduce back-flow from interstitial space to peripheral bloodstream but also could restrict the cellular exocytosis,leading to enhanced intratumoral retention.In vitro studies demonstrated that GNPs-A&C possessed an excellent legumain responsiveness and the increased size was closely relevant with legumain expression.In vivo studies demonstrated GNPs-A&C possessed slower clearance rate and much higher intratumoral retention within legumain-overexpressed tumor compared to non-aggregable NPs,regardless of intravenous or intratumoral injection.More importantly,this delivery platform significantly improved the chemotherapeutic effect of doxorubicin(DOX)towards subcutaneous xenograft C6 tumor.The effectiveness of this stimulus-responsive aggregable delivery system provides a thinking for designing more intelligent size-tunable nanomedicine that can substantially improve intratumoral retention.展开更多
Multidrug resistance proteins （MDRPs）, which are implicated in the mediation of multidrug resistance in tumors, represent the main obstacle to successful chemotherapy. As curcurnin （Cur） exerts inhibitory effects ...Multidrug resistance proteins （MDRPs）, which are implicated in the mediation of multidrug resistance in tumors, represent the main obstacle to successful chemotherapy. As curcurnin （Cur） exerts inhibitory effects on both the expression and function of MDRPs, a nanocarrier for the co-delivery of Cur and doxorubicin （DOX） was prepared to overcome MDR tumors through their synergistic effects. Owing to the overexpression of legumain in tumors, the release profile of DOX from this nanocarrier was designed to be legumain modulated, which was achieved by bridging DOX to a basic material （chitosan） with a legumain- sensitive peptide. Compared with nanoparticles that only contain DOX, the coadministration of DOX and Cur significantly inhibited multidrug resistance （P 〈 0.05） in a multidrug-resistant cancer cell model （MCF-7/ADR cell line）, with cytotoxicity to normal cells （L929 cell line）. Such inhibition could be ascribed to the increased DOX accumulation in the MCF-7/ADR nucleus. The co-delivery system exhibited good anticancer effects through prolonged circulation time, improved tumor-targeting efficiency, elevation of the tumor inhibition activity, and the suppression of MDRP expression. These data revealed the enormous potential of this co-delivery system for cancer therapy, especially in the later stages where multidrug resistance may develop.展开更多
基金supported by the following grants and programs:G.Z.received the grants(Nos.81770183 and 81970155)from the National Natural Science Foundation of China(NSFC,http://www.nsfc.gov.cn/english/site_1/index.html)the CAMS Innovation Fund for Medical Sciences(CIFMS)program(No.2016-I2M-2-006)from Chinese Academy of Medical Sciences&Peking Union Medical College(CAMS,http://english.cams.cn/index.html)+1 种基金L.W.received the program(No.2017-I2M-1-015)from the CIFMSG.Z.was a recipient of the New Century Excellent Talents in University(No.NCET-08-0329)from the Ministry of Education of the People’s Republic of China(http://en.moe.gov.cn/).
文摘Legumain is a C13 family cysteine protease.It plays diverse roles under both physiological and pathological conditions.The high-level expression of legumain is detected in solid tumors.Legumain promotes the proliferation and migration of tumor cells.However,the effect of legumain in blood diseases has not been established.In this report,we studied the effect of legumain on leukemia cells by overexpressing it in THP1 cells.The results demonstrated that legumain promoted cell proliferation,whereas it had little effect on cell apoptosis.Furthermore,legumain promoted the migration of THP1 cells.It was worth noting that legumain decreased the stemness of THP1 cells.Further evidence showed that legumain decreased the expression of Oct4,Sox2,Myc in THP1 cells.Our study reveals the multifaced effects of legumain in leukemia cells and broadens the knowledge of legumain in malignancies.
基金supported by the Beijing Natural Science Foundation(No.L222128)Beijing Institute of Technology Research Fund Program for Young Scholars(No.XSQD-202121010)National Natural Science Foundation of China(No.81961138009)。
文摘Insufficient intratumoral retention of nanomedicines remains the major challenge for broad implementation in clinical sets.Herein,we proposed a legumain-triggered aggregable gold nanoparticle(GNP)delivery platform(GNPs-A&C).GNPs-A&C could form intratumoral or intracellular aggregates in response to the overexpressed legumain.The aggregates with size increase not only could reduce back-flow from interstitial space to peripheral bloodstream but also could restrict the cellular exocytosis,leading to enhanced intratumoral retention.In vitro studies demonstrated that GNPs-A&C possessed an excellent legumain responsiveness and the increased size was closely relevant with legumain expression.In vivo studies demonstrated GNPs-A&C possessed slower clearance rate and much higher intratumoral retention within legumain-overexpressed tumor compared to non-aggregable NPs,regardless of intravenous or intratumoral injection.More importantly,this delivery platform significantly improved the chemotherapeutic effect of doxorubicin(DOX)towards subcutaneous xenograft C6 tumor.The effectiveness of this stimulus-responsive aggregable delivery system provides a thinking for designing more intelligent size-tunable nanomedicine that can substantially improve intratumoral retention.
基金The authors acknowledge the National Natural Science Foundation of China （No. 31600807）, the Natural Science Foundation of Zhejiang Province （No. LQ15H120003）, the National Key Research and Development Plan Project （No. 2016YFC1101201）, and the Science and Technology Planning Project of Wenzhou City （No. Y20160085） for their financial support.
文摘Multidrug resistance proteins （MDRPs）, which are implicated in the mediation of multidrug resistance in tumors, represent the main obstacle to successful chemotherapy. As curcurnin （Cur） exerts inhibitory effects on both the expression and function of MDRPs, a nanocarrier for the co-delivery of Cur and doxorubicin （DOX） was prepared to overcome MDR tumors through their synergistic effects. Owing to the overexpression of legumain in tumors, the release profile of DOX from this nanocarrier was designed to be legumain modulated, which was achieved by bridging DOX to a basic material （chitosan） with a legumain- sensitive peptide. Compared with nanoparticles that only contain DOX, the coadministration of DOX and Cur significantly inhibited multidrug resistance （P 〈 0.05） in a multidrug-resistant cancer cell model （MCF-7/ADR cell line）, with cytotoxicity to normal cells （L929 cell line）. Such inhibition could be ascribed to the increased DOX accumulation in the MCF-7/ADR nucleus. The co-delivery system exhibited good anticancer effects through prolonged circulation time, improved tumor-targeting efficiency, elevation of the tumor inhibition activity, and the suppression of MDRP expression. These data revealed the enormous potential of this co-delivery system for cancer therapy, especially in the later stages where multidrug resistance may develop.
