title: Choline Derivate-Modified Doxorubicin Loaded Micelle for Glioma Therapy.
abstract: Ligand-mediated polymeric micelles have enormous potential for improving the efficacy of glioma therapy. Linear-dendritic drug-polymer conjugates composed of doxorubicin (DOX) and polyethylene glycol (PEG) were synthesized with or without modification of choline derivate (CD). The resulting MeO-PEG-DOX8 and CD-PEG-DOX8 could self-assemble into polymeric micelles with a nanosized diameter around 30 nm and a high drug loading content up to 40.6 and 32.3%, respectively. The optimized formulation 20% CD-PEG-DOX8 micelles had superior cellular uptake and antitumor activity against MeO-PEG-DOX8 micelles. The subcellular distribution using confocal study revealed that 20% CD-PEG-DOX8 micelles preferentially accumulated in the mitochondria. Pharmacokinetic study showed area under the plasma concentration-time curve (AUC0-t) and Cmax for 20% CD-PEG-DOX8 micelles and DOX solution were 1336.58 ± 179.43 mg/L·h, 96.35 ± 3.32 mg/L and 1.40 ± 0.19 mg/L·h, 1.15 ± 0.25 mg/L, respectively. Biodistribution study showed the DOX concentration of 20% CD-PEG-DOX8 micelles treated group at 48 h was 2.37-fold higher than that of MeO-PEG-DOX8 micelles treated group at 48 h and was 24 fold-higher than that of DOX solution treated group at 24 h. CD-PEG-DOX8 micelles (20%) were well tolerated with reduced cardiotoxicity, as evaluated in the body weight change and HE staining studies, while they induced most significant antitumor activity with longest media survival time in an orthotopic mouse model of U87-luci glioblastoma model as displayed in the bioluminescence imaging and survival curve studies. Our findings consequently indicated that 20% CD-PEG-DOX8 micelles are promising drug delivery system for glioma chemotherapy.
authors.affiliation: Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Clinical Pharmacy and Pharmaceutical Management, School of Pharmacy, Fudan University 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Huiying
authors.initials: H
authors.lastname: Yang
authors.affiliation: Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Xutao
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Yubo
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Sai
authors.initials: S
authors.lastname: An
authors.affiliation: Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Haojun
authors.initials: H
authors.lastname: Ma
authors.affiliation: Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University 826 Zhangheng Road, Shanghai 201203, China.
authors.forename: Xi
authors.initials: X
authors.lastname: He
authors.affiliation: Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education, Department of Pharmaceutics, School of Pharmacy, Fudan University 826 Zhangheng Road, Shanghai 201203, China.|State Key Laboratory of Medical Neurobiology, Fudan University , Shanghai 201203, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy*; D002794:Choline / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics; D005434:Flow Cytometry; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D051379:Mice; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry; D066244:Proton Magnetic Resonance Spectroscopy; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000378:metabolism; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D011092:Polyethylene Glycols; D004317:Doxorubicin; D002794:Choline
keywords: choline derivate; doxorubicin; drug−polymer conjugate; glioma; linear−dendritic; polymeric micelles