title: Construction and evaluation of PAMAM-DOX conjugates with superior tumor recognition and intracellular acid-triggered drug release properties.
abstract: An ideal drug delivery system for cancer therapy should be equipped with extended circulation, improved tumor targeting and controlled drug release, as well as low toxicity from the carrier. In this study, a multifunctional drug delivery system based on the PEGylated poly(amidoamine) (PAMAM) dendrimer was designed, and folate-PEGylation was applied to modify the dendrimer in order to enhance tumor selectivity. A series of acid-labile PAMAM-DOX conjugates (FPP-hyd-DOX) with different FA ligand ratios were successfully constructed. (1)H NMR, FTIR, DLS and TEM were used to describe the physicochemical characterization of PAMAM-DOX conjugates. Both in vitro drug release assay and subcellular localization, the conjugates exhibited an obvious pH-triggered drug release. The FPP-hyd-DOX 16/1 displayed much lower IC50 value than that of non-targeted PP-hyd-DOX. Through fluorescence microscopy and flow cytometry investigations, the cellular uptake of FPP-hyd-DOX 16/1 was obviously enhanced, compared with that of PP-hyd-DOX. The cellular uptake mechanism and subcellular localization study revealed that the conjugates were internalized by KB cells via FA receptor and clathrin co-mediated endocytosis, delivered to acidic lysosomes and triggered the release of DOX into nuclei to exert its cytotoxicity. These obtained results showed that FPP-hyd-DOX conjugations would be a promising drug delivery carrier for targeted cancer therapy.
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China; School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: chendawei@suda.edu.cn.
authors.forename: Dawei
authors.initials: D
authors.lastname: Chen
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry*; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry*; D006801:Humans; D046529:Microscopy, Electron, Transmission; D009369:Neoplasms / Q000188:drug therapy*; D066244:Proton Magnetic Resonance Spectroscopy; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000903:Antibiotics, Antineoplastic; D050091:Dendrimers; C104700:PAMAM Starburst; D004317:Doxorubicin
keywords: Active targeting; Doxorubicin; PAMAM; Tumor microenvironment; pH-sensitive