title: RGD-modified PEG-PAMAM-DOX conjugates: in vitro and in vivo studies for glioma.
abstract: This work was based on our recent studies that a promising conjugate, RGD-modified PEGylated polyamidoamine (PAMAM) dendrimer with doxorubicin (DOX) conjugated by acid-sensitive cis-aconityl linkage (RGD-PPCD), could increase tumor targeting by binding with the integrin receptors overexpressed on tumor cells and control release of free DOX in weakly acidic lysosomes. To explore the application of RGD-PPCD to glioma therapy, the effects of the conjugate were further evaluated in glioma model. For comparative studies, DOX was also conjugated to PEG-PAMAM by acid-insensitive succinic linkage to produce the PPSD conjugates, which was further modified by RGD to form RGD-PPSD. In vitro cytotoxicity of the acid-sensitive conjugates against C6 cells was higher than that of the acid-insensitive ones, and further the modification of RGD enhanced the cytotoxicity of the DOX-polymer conjugates as a result of the increased cellular uptake of the RGD-modified conjugates by C6 cells. In vivo pharmacokinetics, biodistribution and antitumor activity were investigated in an orthotopic murine model of C6 glioma by i.v. administration of DOX-polymer conjugates. In comparison with DOX solution, all the conjugates showed significantly prolonged half-life and increased AUC and exhibited higher accumulation in brain tumor than normal brain tissue. Although RGD-PPCD was more than 2-fold lower tumor accumulation than RGD-PPSD, it exhibited the longest survival times among all treatment groups, and therefore, RGD-PPCD conjugate provide a desirable candidate for targeted therapy of glioma.
authors.affiliation: Department of Pharmaceutics, Fudan Univeristy, Shanghai, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhang
authors.forename: Saijie
authors.initials: S
authors.lastname: Zhu
authors.forename: Lili
authors.initials: L
authors.lastname: Qian
authors.forename: Yuanying
authors.initials: Y
authors.lastname: Pei
authors.forename: Yongming
authors.initials: Y
authors.lastname: Qiu
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006207:Half-Life; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D019802:Succinic Acid / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D050091:Dendrimers; D004337:Drug Carriers; D008081:Liposomes; D009842:Oligopeptides; C522249:PEG-PAMAM; D011092:Polyethylene Glycols; C047981:arginyl-glycyl-aspartic acid; D004317:Doxorubicin; D019802:Succinic Acid