title: Drug pH-sensitive release in vitro and targeting ability of polyamidoamine dendrimer complexes for tumor cells.
abstract: Recently, dendrimers have been widely used in medical applications such as drug delivery and gene transfection. In this study, a pH-sensitive diblock copolymer of poly(methacryloyl sulfadimethoxine) (PSD) and polyethylene glycol (PEG) modified by lactose (LA-PEG-b-PSD) was synthesized. The pK(a) value of the LA-PEG-b-PSD was also measured. Then, polyamidoamine (PAMAM) complexes were prepared with PAMAM (G4.0) and LA-PEG-b-PSD by electrostatic interaction. To investigate drug pH-sensitive release in vitro, doxorubicin (DOX) was loaded in PAMAM. A higher drug cumulative release from LA-PEG-b-PSD/PAMAM complexes in phosphate buffered saline (PBS) was found at pH 6.5 than at pH 7.4. The cytotoxicity and cellular uptake of PAMAM complexes were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and confocal microscopy. LA-PEG-b-PSD/PAMAM/DOX complexes were able to enhance the cytotoxicity of DOX against HepG2 cells at pH 7.4. Confocal microscopy showed a higher cellular uptake of PEG-b-PSD/PAMAM complexes at pH 6.5. PAMAM complexes modified by lactose showed a higher affinity for hepatic cancer cells than those without lactose at pH 7.4. These results suggest that LA-PEG-b-PSD/PAMAM complexes exhibit selective targeting and cytotoxicity against HepG2 cells. In vivo antitumor studies showed that the LA-PEG-b-PSD/PAMAM/DOX complexes displayed higher antitumor efficacy compared with non-targeted PAMAM/DOX and DOX solution. These results indicate that this strategy should be applicable to the treatment of liver cancers.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.forename: Haiyang
authors.initials: H
authors.lastname: Hu
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhao
authors.forename: Xing
authors.initials: X
authors.lastname: Tang
authors.forename: Dawei
authors.initials: D
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy; D050091:Dendrimers / Q000737:chemistry* / Q000633:toxicity; D004317:Doxorubicin / Q000008:administration & dosage; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007785:Lactose / Q000737:chemistry; D008113:Liver Neoplasms / Q000188:drug therapy; D011092:Polyethylene Glycols / Q000737:chemistry; D013412:Sulfadimethoxine / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D050091:Dendrimers; C104700:PAMAM Starburst; D013412:Sulfadimethoxine; D011092:Polyethylene Glycols; D004317:Doxorubicin; D007785:Lactose