title: Tumor-Specific Multiple Stimuli-Activated Dendrimeric Nanoassemblies with Metabolic Blockade Surmount Chemotherapy Resistance.
abstract: Chemotherapy resistance remains a serious impediment to successful antitumor therapy around the world. However, existing chemotherapeutic approaches are difficult to cope with the notorious multidrug resistance in clinical treatment. Herein, we developed tumor-specific multiple stimuli-activated dendrimeric nanoassemblies with a metabolic blockade to completely combat both physiological barriers and cellular factors of multidrug resistance. With a sophisticated molecular and supramolecular engineering, this type of tumor-specific multiple stimuli-activated nanoassembly based on dendrimeric prodrugs can hierarchically break through the sequential physiological barriers of drug resistance, including stealthy dendritic PEGylated corona to optimize blood transportation, robust nanostructures for efficient tumor passive targeting and accumulation, enzyme-activated tumor microenvironment targeted to deepen tumor penetration and facilitate cellular uptake, cytoplasmic redox-sensitive disintegration for sufficient release of encapsulated agents, and lysosome acid-triggered nucleus delivery of antitumor drugs. In the meantime, we proposed a versatile tactic of a tumor-specific metabolism blockade for provoking several pathways (ATP restriction, apoptotic activation, and anti-apoptotic inhibition) to restrain multiple cellular factors of drug resistance. The highly efficient antitumor activity to drug-resistant MCF-7R tumor in vitro and in vivo supports this design and strongly defeats both physiological barriers and cellular factors of chemotherapy resistance. This work sets up an innovative dendrimeric nanosystem to surmount multidrug resistance, contributing to the development of a comprehensive nanoparticulate strategy for future clinical applications.
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University , Chengdu, Sichuan 610064, P.R. China.
authors.forename: Yachao
authors.identifier: 0000-0003-4792-0915
authors.initials: Y
authors.lastname: Li
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University , Chengdu, Sichuan 610064, P.R. China.
authors.forename: Xianghui
authors.identifier: 0000-0002-8885-0848
authors.initials: X
authors.lastname: Xu
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University , Chengdu, Sichuan 610064, P.R. China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University , Chengdu, Sichuan 610064, P.R. China.
authors.forename: Yunkun
authors.initials: Y
authors.lastname: Li
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University , Chengdu, Sichuan 610064, P.R. China.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University , Chengdu, Sichuan 610064, P.R. China.|College of Materials Science and Engineering, Nanjing Tech University , Nanjing, Jiangsu 210009, P.R. China.
authors.forename: Zhongwei
authors.identifier: 0000-0003-1547-6880
authors.initials: Z
authors.lastname: Gu
mesh_terms: D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D050091:Dendrimers; D011355:Prodrugs; D004317:Doxorubicin; D000255:Adenosine Triphosphate
keywords: deep tumor penetration; dendrimeric prodrugs; metabolic blockade; multidrug resistance reversal; multiresponsive nanoassemblies