title: Acid-responsive PEGylated doxorubicin prodrug nanoparticles for neuropilin-1 receptor-mediated targeted drug delivery.
abstract: Self-assembled prodrug nanoparticles have demonstrated great promise in cancer chemotherapy. In the present study, we developed a new kind of prodrug nanoparticles for targeted drug delivery. PEGylated doxorubicin conjugate with an acid-cleavable cis-aconityl spacer was prepared. Then it was functionalized with a tumor-penetrating peptide, Cys-Arg-Gly-Asp-Lys (CRGDK), providing the prodrug nanoparticles with the specific binding ability to neurophilin-1 receptor. In acid mediums, doxorubicin could be released from the prodrug nanoparticles with an accumulative release around 60% through the acid-triggered hydrolysis of cis-aconityl bond and nanoparticle disassembly. Whereas, drug release was slow under a neutral pH and the accumulative drug release was less than 16%. In the cell culture tests, our prodrug nanoparticles showed enhanced endocytosis and cytotoxicity in cancer cells including HepG2, MCF-7 and MDA-MB-231 cells, but lower cytotoxicity in human cardiomyocyte H2C9. In the animal experiments, the prodrug nanoparticles were intravenously injected into Balb/c nude mice bearing MDA-MB-231 tumors. Enhanced drug penetration and accumulation in tumors, accompanying with a rapid early tumor-binding behavior, was observed after intravenous injection of the peptide modified prodrug nanoparticles. These data suggests that the acid-sensitive and tumor-targeting PEGylated doxorubicin prodrug nanoparticle may be an efficient drug delivery system for cancer chemotherapy.
authors.affiliation: Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
authors.forename: Huijuan
authors.initials: H
authors.lastname: Song
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin 300071, China.
authors.forename: Ju
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China. Electronic address: wwwangtj@163.com.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Wang
authors.affiliation: School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China.
authors.forename: Pingsheng
authors.initials: P
authors.lastname: Huang
authors.affiliation: Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Tianjin Key Laboratory of Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.affiliation: Tianjin Key Laboratory of Biomaterial Research, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300192, China; State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin 300071, China. Electronic address: kongdeling@hotmail.com.
authors.forename: Deling
authors.initials: D
authors.lastname: Kong
mesh_terms: D000143:Acids / Q000737:chemistry*; D000327:Adsorption; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles; D039942:Neuropilin-1 / Q000502:physiology*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D017550:Spectroscopy, Fourier Transform Infrared; D013816:Thermodynamics
chemical_list: D000143:Acids; D000903:Antibiotics, Antineoplastic; D011355:Prodrugs; D039942:Neuropilin-1; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Cancer chemotherapy; Doxorubicin; Prodrug nanoparticle; pH-sensitive