title: PEG-b-PCL copolymer micelles with the ability of pH-controlled negative-to-positive charge reversal for intracellular delivery of doxorubicin.
abstract: The application of PEG-b-PCL micelles was dampened by their inherent low drug-loading capability and relatively poor cell uptake efficiency. In this study, a series of novel PEG-b-PCL copolymers methoxy poly(ethylene glycol)-b-poly(ε-caprolactone-co-γ-dimethyl maleamidic acid -ε-caprolactone) (mPEG-b-P(CL-co-DCL)) bearing different amounts of acid-labile β-carboxylic amides on the polyester moiety were synthesized. The chain structure and chemical composition of copolymers were characterized by (1)H NMR, Fourier transform infrared spectroscopy (FT-IR), and gel permeation chromatography (GPC). mPEG-b-P(CL-co-DCL) with critical micellar concentrations (CMCs) of 3.2-6.3 μg/mL could self-assemble into stable micelles in water with diameters of 100 to 150 nm. Doxorubicin (DOX), a cationic hydrophobic drug, was successfully encapsulated into the polymer micelles, achieving a very high loading content due to electrostatic interaction. Then the stability, charge-conversional behavior, loading and release profiles, cellular uptake and in vitro cytotoxicity of free drug and drug-loaded micelles were evaluated. The β-carboxylic amides functionalized polymer micelles are negatively charged and stable in neutral solution but quickly become positively charged at pH 6.0, due to the hydrolysis of β-carboxylic amides in acidic conditions. The pH-triggered negative-to-positive charge reversal not only resulted in a very fast drug release in acidic conditions, but also effectively enhanced the cellular uptake by electrostatic absorptive endocytosis. The MTT assay demonstrated that mPEG-b-P(CL-co-DCL) micelles were biocompatible to HepG2 cells while DOX-loaded micelles showed significant cytotoxicity. In sum, the introduction of acid-labile β-carboxylic amides on the polyester block in mPEG-b-P(CL-co-DCL) exhibited great potentials for the modifications in the stability in blood circulation, drug solubilization, and release properties, as well as cell internalization and intracellular drug release.
authors.affiliation: Department of Polymer Science and Technology and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University , Tianjin 300072, China.
authors.forename: Hongzhang
authors.initials: H
authors.lastname: Deng
authors.forename: Jinjian
authors.initials: J
authors.lastname: Liu
authors.forename: Xuefei
authors.initials: X
authors.lastname: Zhao
authors.forename: Yuming
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Liu
authors.forename: Shuxin
authors.initials: S
authors.lastname: Xu
authors.forename: Liandong
authors.initials: L
authors.lastname: Deng
authors.forename: Anjie
authors.initials: A
authors.lastname: Dong
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007424:Intracellular Fluid / Q000187:drug effects* / Q000378:metabolism; D007783:Lactones / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D008823:Micelles; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry* / Q000378:metabolism; D013499:Surface Properties / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D007783:Lactones; D008823:Micelles; C521904:poly(ethylene glycol)-block-poly(epsilon-caprolactone); D011092:Polyethylene Glycols; D004317:Doxorubicin