title: PEGylated dendritic diaminocyclohexyl-platinum (II) conjugates as pH-responsive drug delivery vehicles with enhanced tumor accumulation and antitumor efficacy.
abstract: Environmentally responsive peptide dendrimers loaded with drugs are suitable candidates for cancer therapy. In this study, we report the preparation and characterization of mPEGylated peptide dendrimer-linked diaminocyclohexyl platinum (II) (dendrimer-DACHPt) conjugates as pH-responsive drug delivery vehicles for tumor suppression in mice. The DACHPt has a molecular structure, is and activity closely related to oxaliplatin and was linked to dendrimer via N,O-chelate coordination. The products were pH-responsive and released drug significantly faster in acidic environments (pH 5.0) than pH 7.4. Consequently, the conjugates suppressed tumor growth better than clinical oxaliplatin(®) without inducing toxicity in an SKOV-3 human ovarian cancer xenograft. Through the systemic delivery of conjugates, 25-fold higher tumor platinum uptake at 36 h post-injection was seen observed due to the enhanced permeability and retention (EPR) effect thereby remarkably enhancing the therapeutic indexes of this small-molecule drug. Thus, the mPEGylated peptide dendrimer-linked DACH-platinum conjugates are novel potential drug delivery systems with implications in future ovarian cancer therapy.
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
authors.forename: Dayi
authors.initials: D
authors.lastname: Pan
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
authors.forename: Wenchuan
authors.initials: W
authors.lastname: She
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Guo
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China. Electronic address: luokui@scu.edu.cn.
authors.forename: Kui
authors.initials: K
authors.lastname: Luo
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.
authors.forename: Qiangying
authors.initials: Q
authors.lastname: Yi
authors.affiliation: National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China. Electronic address: zwgu@scu.edu.cn.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Gu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008657:Metabolic Clearance Rate; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry*; D058726:Nanoconjugates / Q000008:administration & dosage / Q000737:chemistry; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D053769:Nanocapsules; D058726:Nanoconjugates; D009944:Organoplatinum Compounds; D011092:Polyethylene Glycols; C024236:1,2-diaminocyclohexyl platinum sulfate
keywords: Biodistribution; Drug delivery system; Ovarian cancer; Oxaliplatin; Peptide dendrimer; pH-responsive