title: cRGDyK modified pH responsive nanoparticles for specific intracellular delivery of doxorubicin.
abstract: Stimuli-responsive nanocarriers attract wide attention because of the unique differences in microenvironment between solid tumors and normal tissues. Herein, we reported a novel cRGDyK peptide modified pH-sensitive nanoparticle system based on poly(ethylene glycol)-poly(2,4,6-trimethoxy benzylidene-pentaerythritol carbonate) (PEG-PTMBPEC) diblock copolymer, which was expected to destroy tumor angiogenesis and kill tumor cells simultaneously. Doxorubicin (DOX)-loaded nanoparticles (NPs) were characterized to have a uniform size distribution, high entrapment efficiency, good stability in plasma as well as a pH dependent drug release pattern. Blank NPs were non-toxic to both tumor cells and normal cells, while DOX-loaded cRGDyK peptide modified NPs (cRGDyK-NPs) exhibited the pronounced cytotoxicity against B16 cells and human umbilical vein endothelial cells (HUVEC) overexpressing αvβ3 integrin receptors. Cellular uptake studies revealed that the highly efficient uptake of cRGDyK-NPs was attributed to the receptor-mediated endocytosis and acidic-triggered drug release. Importantly, cRGDyK-NPs could dramatically reduce the systemic toxicity of DOX and exert excellent tumor killing activity in vivo. The cRGDyK modified pH-sensitive nanocarrier is a promising vehicle for intracellular drug delivery to αvβ3 integrin receptor overexpressed tumor cells and neovascular cells.
  
  
  CONCLUSIONS
  Slow intracellular drug release and poor tumor targeting capacity are still the critical barriers of polymeric nanoparticles (NPs) for the treatment efficiency of chemotherapy. In the present study, we designed cRGDyK peptide modified poly(ethylene glycol)-poly(2,4,6-trimethoxybenzylidene-pentaerythritol carbonate) (cRGDyK-PEG-PTMBPEC) NPs with active targeting and fast pH-triggered drug release. Doxorubicin (DOX)-loaded cRGDyK-PEG-PTMBPEC NPs exhibited pronounced cytotoxicity and enhanced cellular uptake against B16 cells and human umbilical vein endothelial cells overexpressing αvβ3 integrin receptors. Moreover, the active targeted pH-sensitive NPs can enhance the antitumor activity and reduce the systematic toxicity of DOX in vivo.
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou 215123, PR China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Jiangnan University, Wuxi 214122, PR China.
authors.forename: Lipeng
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou 215123, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou 215123, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou 215123, PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou 215123, PR China.
authors.forename: Chenmin
authors.initials: C
authors.lastname: Tian
authors.affiliation: College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou 215123, PR China.
authors.forename: Wen
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou 215123, PR China.
authors.forename: Lu
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou 215123, PR China.
authors.forename: Jia
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou 215123, PR China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou 215123, PR China; Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: chendawei@syphu.edu.cn.
authors.forename: Dawei
authors.initials: D
authors.lastname: Chen
mesh_terms: D000818:Animals; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D004337:Drug Carriers; D010456:Peptides, Cyclic; C550210:cyclo(Arg-Gly-Asp-Tyr-Lys); D004317:Doxorubicin
keywords: Cellular uptake mechanism; Nanoparticles; Targeting tumor angiogenesis; cRGDyK peptide; pH-sensitive