title: A pH-responsive glycolipid-like nanocarrier for optimising the time-dependent distribution of free chemical drugs in focal cells.
abstract: Though Drug delivery systems have achieved accumulation at tumor sites via passive targeting and active targeting, the therapeutic effects are far from perfect. The unsatisfactory results are mainly due to limited drug release from the nanocarriers at tumor sites, while the pharmacological activities of the drug are attributed to the concentration of the free drug and the time maintained at the pharmacological targets. A pH-responsive chitosan based glycolipid-like nanocarrier (CSO-FBA-SA) was fabricated by conjugating stearyl alcohol (SA) to chitosan oligosaccharide (CSO) with the linkage of 4-formylbenzoic acid (FBA). FBA was a kind of aromatic aldehyde carbonyl compounds, which can form the benzoic-imine bond. In the presence of a Schiff's base structure, the carrier showed improved properties and could be quickly degraded in an acidic environment. In order to explore the process and mechanism of the nanocarriers in focal cells, the method for determining the intracellular concentration of released free doxorubicin was established, and the time-dependent change of the DOX-loaded micelles was revealed. The sight of drug release was also obtained with CLSM. The cytotoxicity of the CSO-FBA-SA/DOX against human breast cancer MCF-7 cells increased by 2.75-fold and 3.77-fold in comparison with the CSO-SA/DOX and DOX, respectively. Furthermore, the CSO-FBA-SA/DOX showed a 2.12-fold higher cytotoxicity against the MCF-7 cells than that treated against human ovarian cancer SKOV-3 cells with lower intracellular pH value, which indicated that the cellular inhibition positively correlated with the intracellular pH value. High tumor accumulation and fast drug release of the CSO-FBA-SA/DOX in tumor was responsible for the remarkable tumor growth inhibitory effect. Moreover, the CSO-FBA-SA/DOX could selectively respond to the acidic environment and release DOX in tumor only, which had relatively minimal cytotoxicity towards normal tissues. The results showed that this newly developed glycolipid-like nanocarrier could act as a potential vector for delivering the drug effectively with a low systemic toxicity.
authors.affiliation: Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, People's Republic of China.
authors.forename: Bolin
authors.initials: B
authors.lastname: Cheng
authors.affiliation: Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, People's Republic of China.
authors.forename: Binbin
authors.initials: B
authors.lastname: Lu
authors.affiliation: Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, People's Republic of China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, People's Republic of China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Meng
authors.affiliation: Ocean College, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, People's Republic of China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Ocean College, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, People's Republic of China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, People's Republic of China.
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.affiliation: Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Pharmacy, School of Medicine Science, Jiaxing University, Zhejiang 314001, People's Republic of China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Huang
authors.affiliation: Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, People's Republic of China. Electronic address: hufq@zju.edu.cn.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Hu
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D048271:Chitosan / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods*; D005233:Fatty Alcohols; D005260:Female; D006017:Glycolipids / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D012545:Schiff Bases
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D005233:Fatty Alcohols; D006017:Glycolipids; D008823:Micelles; D012545:Schiff Bases; C009316:stearyl alcohol; D004317:Doxorubicin; D048271:Chitosan
keywords: Glycolipid-like nanocarriers; PH-responsive; Selectively drug release; Time-dependent distribution