Multidrug-resistance(MDR)featuring complicated and poorly defined mechanisms is a major obstacle to the success of cancer chemotherapy in the clinic.Compound nanoparticles comprising multiple cytostatics with differen...Multidrug-resistance(MDR)featuring complicated and poorly defined mechanisms is a major obstacle to the success of cancer chemotherapy in the clinic.Compound nanoparticles comprising multiple cytostatics with different mechanisms of action are commonly developed to tackle the multifaceted nature of clinical MDR.However,the different pharmacokinetics and release profiles of various drugs result in inconsistent drug internalization and suboptimal drug synergy at the tumor sites.In the present study,a type of self-targeting hyaluronate(HA)nanogels((CDDPH)^ANG/DOX)to reverse drug resistance through the synchronized pharmacokinetics,intratumoral distribution,and intracellular release of topoisomerase II inhibitor doxorubicin(DOX)and DNA-crosslinking agent cisplatin(CDDP)is developed.With prolonged circulation time and enhanced intratumoral accumulation in vivo,(CDDP)^HANG/DOX shows efficient drug delivery into the drug-resistant MCF-7/ADR breast cancer cells and enhanced antitumor activity.Besides,fluorescence imaging of DOX combined with the micro-computed tomography(micro-CT)imaging of CDDP facilitates the visualization of this combination tumor chemotherapy.With visualizable synchronized drug delivery,the self-targeting in situ crosslinked nanoplatform may hold good potential in future clinical therapy of advanced cancers.展开更多
Low accumulation and penetration of nanomedicines in tumor severely reduce therapeutic efficacy.Herein,a pH-responsive gold nanoassembly is designed to overcome these problems.Polyethylene glycol linked raltitrexed(RT...Low accumulation and penetration of nanomedicines in tumor severely reduce therapeutic efficacy.Herein,a pH-responsive gold nanoassembly is designed to overcome these problems.Polyethylene glycol linked raltitrexed(RTX,target ligand and chemotherapy drug)and two tertiary amine molecules(1-(2-aminoethyl)pyrrolidine and N,N-dibutylethylenediamine)are modified on the surface of the 6-nm gold nanoparticles by lipoic acid to form gold nanoassembly defined as Au-NNP(RTX).The Au-NNP(RTX)nanoassembly could remain at about 160 nm at the blood circulation(pH 7.4),while split into 6-nm gold nanoparticles due to tertiary amine protonation at tumor extracellular pH(pH 6.8).This pH-responsive disassembly behavior endows Au-NNP(RTX)better tumor tissue permeability through the better diffusion brought by the size reduction.Meanwhile,after disassembly,more RTXs on the surface of gold nanoparticles are exposed from the shielded state of assembly along with 2.25-fold augment of cellular uptake capability.Most importantly,the results show that Au-NNP(RTX)possesses of high tumor accumulation and effective tumor penetration,thereby enhancing the tumor chemo-radiotherapy efficiency.展开更多
Background:Artesunate(ASA)acts as an•O_(2)^(-)source through the breakdown of en-doperoxide bridges catalyzed by Fe^(2+),yet its efficacy in ASA-based nanodrugs is lim-ited by poor intracellular delivery.Methods:ASA–...Background:Artesunate(ASA)acts as an•O_(2)^(-)source through the breakdown of en-doperoxide bridges catalyzed by Fe^(2+),yet its efficacy in ASA-based nanodrugs is lim-ited by poor intracellular delivery.Methods:ASA–hyaluronic acid(HA)conjugates were formed from hydrophobic ASA and hydrophilic HA by an esterification reaction first,and then self-targeting nanomi-celles(NM)were developed using the fact that the amphiphilic conjugates of ASA and HA are capable of self-assembling in aqueous environments.Results:These ASA–HA NMs utilize CD44 receptor-mediated transcytosis to greatly enhance uptake by breast cancer cells.Subsequently,endogenous Fe^(2+)from the tumor catalyzes the released ASA to produce highly toxic •O_(2)^(-) radicals to kill tumor cells,although sustained tumor growth inhibition can be achieved via in vivo experiments.Conclusions:Self-targeting NMs represent a promising strategy for enhancing ASA-based treatments,leveraging clinically approved drugs to expedite drug development and clinical research in oncology.展开更多
基金This study was financially supported by the National Key Research and Development Program of China(No.2016YFC1100701)the National Natural Science Foundation of China(Nos.52022095,51973216,and 51873207)+1 种基金the Science and Technology Development Program of jilin Province(No.20200404182YY)the Youth Innovation Promotion Association of Chinese Academy of Sciences(No.2019005)。
文摘Multidrug-resistance(MDR)featuring complicated and poorly defined mechanisms is a major obstacle to the success of cancer chemotherapy in the clinic.Compound nanoparticles comprising multiple cytostatics with different mechanisms of action are commonly developed to tackle the multifaceted nature of clinical MDR.However,the different pharmacokinetics and release profiles of various drugs result in inconsistent drug internalization and suboptimal drug synergy at the tumor sites.In the present study,a type of self-targeting hyaluronate(HA)nanogels((CDDPH)^ANG/DOX)to reverse drug resistance through the synchronized pharmacokinetics,intratumoral distribution,and intracellular release of topoisomerase II inhibitor doxorubicin(DOX)and DNA-crosslinking agent cisplatin(CDDP)is developed.With prolonged circulation time and enhanced intratumoral accumulation in vivo,(CDDP)^HANG/DOX shows efficient drug delivery into the drug-resistant MCF-7/ADR breast cancer cells and enhanced antitumor activity.Besides,fluorescence imaging of DOX combined with the micro-computed tomography(micro-CT)imaging of CDDP facilitates the visualization of this combination tumor chemotherapy.With visualizable synchronized drug delivery,the self-targeting in situ crosslinked nanoplatform may hold good potential in future clinical therapy of advanced cancers.
基金This study is dedicated to 100th anniversary of Chemistry at Nankai University.This work was supported by the National Natural Science Foundation of China(Grant 52073147,51773096,51433004,32071342)Specific Program for High-Tech Leader&Team of Tianjin Government,Tianjin innovation and Promotion Plan Key Innovation Team of Immunoreactive Biomaterials.We appreciate Prof.Qiang Wu at Nankai University for help with the characterization of materials and Dr.Ding Yuxun for help with characterization of penetration.
文摘Low accumulation and penetration of nanomedicines in tumor severely reduce therapeutic efficacy.Herein,a pH-responsive gold nanoassembly is designed to overcome these problems.Polyethylene glycol linked raltitrexed(RTX,target ligand and chemotherapy drug)and two tertiary amine molecules(1-(2-aminoethyl)pyrrolidine and N,N-dibutylethylenediamine)are modified on the surface of the 6-nm gold nanoparticles by lipoic acid to form gold nanoassembly defined as Au-NNP(RTX).The Au-NNP(RTX)nanoassembly could remain at about 160 nm at the blood circulation(pH 7.4),while split into 6-nm gold nanoparticles due to tertiary amine protonation at tumor extracellular pH(pH 6.8).This pH-responsive disassembly behavior endows Au-NNP(RTX)better tumor tissue permeability through the better diffusion brought by the size reduction.Meanwhile,after disassembly,more RTXs on the surface of gold nanoparticles are exposed from the shielded state of assembly along with 2.25-fold augment of cellular uptake capability.Most importantly,the results show that Au-NNP(RTX)possesses of high tumor accumulation and effective tumor penetration,thereby enhancing the tumor chemo-radiotherapy efficiency.
基金We acknowledge the financial support from the National Natural Science Foundation of China(82000152)Key Research and Development Program in Xinjiang Uygur Autonomous Region(2023B02030 and 2023B02030-1)+2 种基金Autonomous Region Universities Basic Research Funds Research Projects-Cultivation Projects(XJEDU2023P017)Natural Science Foundation of Xinjiang Uygur Autonomous Region(2022D01C698)the Xinjiang Uygur Autonomous Region Tianchi Talent Introduction Program-Young Doctor(51052300514).
文摘Background:Artesunate(ASA)acts as an•O_(2)^(-)source through the breakdown of en-doperoxide bridges catalyzed by Fe^(2+),yet its efficacy in ASA-based nanodrugs is lim-ited by poor intracellular delivery.Methods:ASA–hyaluronic acid(HA)conjugates were formed from hydrophobic ASA and hydrophilic HA by an esterification reaction first,and then self-targeting nanomi-celles(NM)were developed using the fact that the amphiphilic conjugates of ASA and HA are capable of self-assembling in aqueous environments.Results:These ASA–HA NMs utilize CD44 receptor-mediated transcytosis to greatly enhance uptake by breast cancer cells.Subsequently,endogenous Fe^(2+)from the tumor catalyzes the released ASA to produce highly toxic •O_(2)^(-) radicals to kill tumor cells,although sustained tumor growth inhibition can be achieved via in vivo experiments.Conclusions:Self-targeting NMs represent a promising strategy for enhancing ASA-based treatments,leveraging clinically approved drugs to expedite drug development and clinical research in oncology.
