title: Design and evaluation of pH-sensitive liposomes constructed by poly(2-ethyl-2-oxazoline)-cholesterol hemisuccinate for doxorubicin delivery.
abstract: In this study, a novel material, poly(2-ethyl-2-oxazoline)-cholesterol hemisuccinate (PEtOz-CHEMS), was synthesized to construct pH-sensitive liposomes. The structure of PEtOz-CHEMS was confirmed by thin-layer chromatography, Fourier transform infrared spectroscopy, and (1)H NMR. Anticancer fluorescent drug doxorubicin (DOX) was encapsulated into the liposomes. Compared with conventional liposomes (CL), CHEMS modified liposomes (CH-L) and PEGylated liposomes (PEG-L), the PEtOzylated liposomes (PEtOz-L) showed an acidic pH-induced increase in particle size. At pH 6.4, the heme release of PEtOz-L group was close to that of the positive control group, whereas that of CL, CH-L and PEG-L was close to that of the negative control group. In vitro drug release studies demonstrated that DOX was released from PEtOz-L in a pH-dependent manner, and the release of DOX from conventional DOX liposomes (CL-DOX), DOX loaded CH-L (CH-DOX-L) and PEGylated DOX liposomes (PEG-DOX-L) had no pronounced differences under each pH medium. In vitro cellular uptake assays showed that PEtOz-DOX-L indicated a significant fluorescence intensity at pH 6.4 compared with at pH 7.4. CL-DOX, CH-DOX-L and PEG-DOX-L did not achieve any obvious diversity at different pH conditions. Confocal laser scanning microscopy images showed that PEtOz-DOX-L can fuse with the endosomal membrane under acidic conditions of endosome, release DOX into the cytoplasm, then gather into the nucleus. Therefore, PEtOz can help liposomes achieve "endosomal escape". The in vitro cytotoxicity experiment results on A375 cells showed that PEtOz-DOX-L resulted in lower cell viability than CL-DOX, CH-DOX-L and PEG-DOX-L under low pH conditions. These results confirm that the pH-responsive PEtOz was a promising material for intracellular targeted delivery system and might be used for overcoming the "PEG dilemma".
authors: Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, PR China. Electronic address: huan.xu1@163.com.
authors: Huan
authors: H
authors: Xu
authors: Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, PR China.
authors: Meina
authors: M
authors: Hu
authors: Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, PR China.
authors: Xiu
authors: X
authors: Yu
authors: Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, PR China.
authors: Yan
authors: Y
authors: Li
authors: Department of Anatomy, College of Basic Medical Science, Dlian Medical University, Dalian, PR China. Electronic address: fuyuanshan@163.com.
authors: Yuanshan
authors: Y
authors: Fu
authors: Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, PR China.
authors: Xiaoxia
authors: X
authors: Zhou
authors: Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, PR China.
authors: Di
authors: D
authors: Zhang
authors: Department of Pharmacy, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian, PR China.
authors: Jianying
authors: J
authors: Li
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000737:chemistry; D002788:Cholesterol Esters / Q000138:chemical synthesis / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology; D016503:Drug Delivery Systems; D065546:Drug Liberation; D004705:Endocytosis / Q000187:drug effects; D011992:Endosomes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008081:Liposomes; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008561:Membrane Fusion / Q000187:drug effects; D018613:Microscopy, Confocal; D015394:Molecular Structure; D010316:Particle Size; D011073:Polyamines / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D000903:Antibiotics, Antineoplastic; D002788:Cholesterol Esters; D008081:Liposomes; D011073:Polyamines; C511916:poly(2-ethyl-2-oxazoline); C000603662:poly(2-ethyl-2-oxazoline)-cholesterol hemisuccinate; D004317:Doxorubicin; D002784:Cholesterol
keywords: Cholesterol hemisuccinate; Liposomes; PEG dilemma; PEGylation; Poly(2-ethyl-2-oxazoline); pH-sensitive