title: Study of the pH-sensitive mechanism of tumor-targeting liposomes.
abstract: Currently, the phosphatidylethanolamine-based, pH-sensitive, liposome drug-delivery system has been widely developed for efficient, targeted cancer therapy. However, the mechanism of pH sensitivity was unclear; it is a main obstacle in controlling the preparation of pH-sensitive liposomes (PSLs).Therefore, our research is aimed at clarifying the pH-response mechanism of the various molecules that compose liposomes. We chose the small pH-sensitive molecules oleic acid (OA), linoleic acid (LA) and cholesteryl hemisuccinate (CHEMS) and the fundamental lipids cholesterol and phosphatidylethanolamine (PE) as test molecules. The PSLs were prepared using the thin-film hydration method and characterized in detail at various pH values (pH 5.0, 6.0 and 7.4), including particle size, ζ-potential, drug encapsulation efficiency and drug loading. The surface structure was observed by transmission electron microscopy (TEM), and the electrical conductivity of the liposome dispersion was also tested. The calorimetric analysis was conducted by Nano-differential scanning calorimetry (Nano-DSC). The in vitro drug release profile showed that PSLs exhibit good pH sensitivity. At neutral pH, the particle size was approximately 150nm, and it dramatically increased at pH 5.0. The ζ-potential increased as the pH decreased. The Nano-DSC results showed that cholesterol and CHEMS can both increase the stability and phase transfer temperature of PSLs. Conductivity increased to a maximum at pH 5.0 and was rather low at pH 7.4. In conclusion, results show that the three kinds of liposomes have pH responsive release characteristics in acidic pH. The OA-PSLs have a pH sensitive point of 5. Since CHEMS has a cholesterol-like structure, it can stabilizes the phospholipid bilayer under neutral conditions as shown in the Nano-DSC data, and because it has a special steroidal rigid structure, it exhibits better pH response characteristics under acidic conditions.
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 Wenhuaxi Road, Jinan 250012, PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Fan
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 Wenhuaxi Road, Jinan 250012, PR China.
authors.forename: Cong
authors.initials: C
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 Wenhuaxi Road, Jinan 250012, PR China.
authors.forename: Yiheng
authors.initials: Y
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 Wenhuaxi Road, Jinan 250012, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 Wenhuaxi Road, Jinan 250012, PR China. Electronic address: guimeilin@sdu.edu.cn.
authors.forename: Guimei
authors.initials: G
authors.lastname: Lin
mesh_terms: D002152:Calorimetry, Differential Scanning; D002788:Cholesterol Esters / Q000737:chemistry; D016503:Drug Delivery Systems; D004553:Electric Conductivity; D006358:Hot Temperature; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019787:Linoleic Acid / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry*; D046529:Microscopy, Electron, Transmission; D036103:Nanotechnology / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019301:Oleic Acid / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry; D013499:Surface Properties; D013696:Temperature; D059016:Tumor Microenvironment
chemical_list: D002788:Cholesterol Esters; D008081:Liposomes; D010714:Phosphatidylethanolamines; D019301:Oleic Acid; C483858:phosphatidylethanolamine; D019787:Linoleic Acid; C013440:cholesteryl succinate
keywords: Drug delivery; Nano-DSC; Phase transition; Tumor mileu response; pH-sensitive liposome