title: Self-Assembling Doxorubicin Prodrug Forming Nanoparticles and Effectively Reversing Drug Resistance In Vitro and In Vivo.
abstract: Doxorubicin (DOX) is a widely used chemotherapeutic drug to treat a range of cancers. However, its unfavorable effects, particularly the cardiotoxicity and the induction of multidrug resistance (MDR), significantly limit its clinical applications. Herein, a novel doxorubicin prodrug, PEG2K-DOX, is synthesized by conjugating a deprotonated doxorubicin molecule with the polyethylene glycol (PEG, MW: 2K) chain via pH-responsive hydrazone bond, and its potential as a better alternative than doxorubicin is evaluated. The data show that the amphiphilic PEG2K-DOX can self-assemble into stable nanoparticles with a high and fixed doxorubicin loading content (≈20 wt%), a favorable size of 91.5 nm with a narrow polydispersity (PDI = 0.14), good stability, and pH-dependent release behavior due to the acid-cleavable linkage between PEG and doxorubicin. Although doxorubicin hardly accumulates in MDR cells, PEG2K-DOX nanoparticles significantly increase the cellular uptake and cell-killing activity of doxorubicin in two MDR cancer cell lines MCF-7/ADR and KBv200, with the IC50values dropped to 1.130% and 42.467% of doxorubicin, respectively. More impressively, PEG2K-DOX nanoparticles exhibit significantly improved plasma pharmacokinetics, increased in vivo therapeutic efficacy against MDR xenograft tumors, and better in vivo safety compared with doxorubicin. PEG2K-DOX nanoparticles hold the promise to become a better alternative than doxorubicin for cancer treatment, especially for MDR tumors.
authors.affiliation: College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, China.
authors.forename: Xiaoman
authors.initials: X
authors.lastname: Mao
authors.affiliation: Center for Cancer Biology and Innovative Therapeutics, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou, 310014, China.
authors.forename: Jingxing
authors.initials: J
authors.lastname: Si
authors.affiliation: College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, China.|Center for Cancer Biology and Innovative Therapeutics, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou, 310014, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Collaborative Innovation Center for Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, 310014, China.
authors.forename: Xuanrong
authors.initials: X
authors.lastname: Sun
authors.affiliation: College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, China.|Center for Cancer Biology and Innovative Therapeutics, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou, 310014, China.
authors.forename: Qianzhi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, China.
authors.forename: Youqing
authors.initials: Y
authors.lastname: Shen
authors.affiliation: College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, China.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Tang
authors.affiliation: College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, China.
authors.forename: Xiangrui
authors.initials: X
authors.lastname: Liu
authors.affiliation: College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, 310027, China. suim@zju.edu.cn.|Center for Cancer Biology and Innovative Therapeutics, Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Clinical Research Institute, Zhejiang Provincial People's Hospital, Hangzhou, 310014, China. suim@zju.edu.cn.
authors.forename: Meihua
authors.initials: M
authors.lastname: Sui
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry* / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004337:Drug Carriers; D011355:Prodrugs; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: doxorubicin; multidrug resistance; nanoparticles; self-assembly; sensitization