title: Stepwise pH-responsive nanoparticles containing charge-reversible pullulan-based shells and poly(β-amino ester)/poly(lactic-co-glycolic acid) cores as carriers of anticancer drugs for combination therapy on hepatocellular carcinoma.
abstract: Stepwise pH-responsive nanoparticle system containing charge reversible pullulan-based (CAPL) shell and poly(β-amino ester) (PBAE)/poly(lactic-co-glycolic acid) (PLAG) core is designed to be used as carriers of paclitaxel (PTX) and combretastatin A4 (CA4) for combining antiangiogenesis and chemotherapy to treat hepatocellular carcinoma (HCC). CAPL-coated PBAE/PLGA (CAPL/PBAE/PLGA) nanoparticles displayed step-by-step responses to weakly acidic tumor microenvironment (pH ≈6.5) and endo/lysosome (pH ≈5.5) respectively through the cleavage of β-carboxylic amide bond in CAPL and the "proton-sponge" effect of PBAE, thus realized the efficient and orderly releases of CA4 and PTX. In human HCC HepG2 cells and human umbilical vein endothelial cells, CAPL/PBAE/PLGA nanoparticles significantly enhanced synergistic effects of PTX and CA4 on cell proliferation and cell migration. In HepG2 tumor-bearing mice, CAPL/PBAE/PLGA nanoparticles showed excellent tumor-targeting capability and remarkably increased inhibitory effects of PTX and CA4 on tumor growth and angiogenesis. In conclusion, this novel nanoparticle system is a promising candidate as carrier for drugs against HCC.
authors.affiliation: School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Tong
authors.initials: T
authors.lastname: An
authors.affiliation: School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Guoyun
authors.initials: G
authors.lastname: Wan
authors.affiliation: Tianjin Key Laboratory of Biomedical Materials, Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, PR China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Hemei
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Sipei
authors.initials: S
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Rongshan
authors.initials: R
authors.lastname: Li
authors.affiliation: School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Yang
authors.affiliation: School of Pharmacy, Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), Tianjin Medical University, Tianjin 300070, PR China. Electronic address: wangyinsong@tmu.edu.cn.
authors.forename: Yinsong
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000737:chemistry*; D005936:Glucans / Q000737:chemistry*; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000737:chemistry; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D017239:Paclitaxel / Q000008:administration & dosage* / Q000627:therapeutic use; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry; D013267:Stilbenes / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D005936:Glucans; D011108:Polymers; D013267:Stilbenes; C507253:poly(beta-amino ester); D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C009109:pullulan; C058728:fosbretabulin; D017239:Paclitaxel
keywords: Combination therapy; Hepatocellular carcinoma; PBAE/PLGA; Pullulan; Stepwise pH-responsive nanoparticle