title: Angiopep-2-conjugated poly(ethylene glycol)-co- poly(ε-caprolactone) polymersomes for dual-targeting drug delivery to glioma in rats.
abstract: The blood-brain barrier is a formidable obstacle for glioma chemotherapy due to its compact structure and drug efflux ability. In this study, a dual-targeting drug delivery system involving Angiopep-2-conjugated biodegradable polymersomes loaded with doxorubicin (Ang-PS-DOX) was developed to exploit transport by the low-density lipoprotein receptor-related protein 1 (LRP1), which is overexpressed in both blood-brain barrier and glioma cells. The polymersomes (PS) were prepared using a thin-film hydration method. The PS were loaded with doxorubicin using the pH gradient method (Ang-PS-DOX). The resulting PS were uniformly spherical, with diameters of ~135 nm and with ~159.9 Angiopep-2 molecules on the surface of each PS. The drug-loading capacity and the encapsulation efficiency for doxorubicin were 7.94%±0.17% and 95.0%±1.6%, respectively. Permeability tests demonstrated that the proton diffusion coefficient across the PS membrane was far slower than that across the liposome membrane, and the common logarithm value was linearly dependent on the dioxane content in the external phase. Compared with PS-DOX, Ang-PS-DOX demonstrated significantly higher cellular uptake and stronger cytotoxicity in C6 cells. In vivo pharmacokinetics and brain distribution experiments revealed that Ang-PS-DOX achieved a more extensive distribution and more abundant accumulation in glioma cells than PS-DOX. Moreover, the survival time of glioma-bearing rats treated with Ang-PS-DOX was significantly prolonged compared with those treated with PS-DOX or a solution of free doxorubicin. These results suggested that Ang-PS-DOX can target glioma cells and enhance chemotherapeutic efficacy.
authors.affiliation: Department of Pharmacy, Xianju People's Hospital, Xianju, Zhejiang; Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai.
authors.forename: Fei
authors.initials: F
authors.lastname: Lu
authors.affiliation: Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai; Chongyang Center for Disease Control and Prevention, Xianning, Hubei.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Pang
authors.affiliation: Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: School of Life Science, Fudan University, Shanghai, People's Republic of China.
authors.forename: Kai
authors.initials: K
authors.lastname: Jin
authors.affiliation: Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai.
authors.forename: Haichun
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Pang
authors.affiliation: Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai.
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, Key Laboratory of Smart Drug Delivery, Ministry of Education and PLA, School of Pharmacy, Fudan University, Shanghai.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Pang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D020285:Cryoelectron Microscopy / Q000379:methods; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D005910:Glioma / Q000188:drug therapy*; D006863:Hydrogen-Ion Concentration; D008297:Male; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry*; D010539:Permeability; D011091:Polyesters / Q000008:administration & dosage / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry*; D017208:Rats, Wistar; D011973:Receptors, LDL / Q000378:metabolism
chemical_list: C531860:Angiopep-2; D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D010455:Peptides; D011091:Polyesters; D011973:Receptors, LDL; C000617025:polycaprolactone-g-polyethylene glycol; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Angiopep-2; biodegradable polymersomes; doxorubicin; dual targeting; glioma treatment