title: Nanomicelles based on X-shaped four-armed peglyated distearylglycerol as long circulating system for doxorubicin delivery.
abstract: A novel X-shaped four-armed gemini-like peglyated distearylglycerol (Gemini-PEG2K-GCDS), with two hydrophilic PEG heads and two hydrophobic stearic acid tails, was successfully synthesized and used as a nanomicellar carrier for delivery of doxorubicin. The critical micelle concentration of the amphiphilic copolymer was higher than 10(-6). Mean particle size and zeta potential of DOX-encapsulated Gemini-PEG2K-GCDS nanomicelles (DOX-GNMs) was 20.4nm and+3.91mv, respectively. Encapsulation efficiency of DOX-GNMs was as high as 94.6 and DOX release was pH-dependent from DOX-GNMs, ensuring the stability of nanomicelles in blood circulation and rapid release of DOX in tumor cells. Pharmacokinetic studies in rats following i.v. administration, DOX-GNMs demonstrated longer retention in blood and larger AUC (19.1-fold of t1/2 and 12.9-fold of AUC) compared with DOX solutions (DOX-Sol). Tissue distribution studies indicate that DOX-GNMs had higher tumor accumulation (4.6-fold) and lower heart toxicity in H22 tumor-bearing mice (17.4-fold) at 48h after administration in comparison with DOX-Sol. Moreover, IC50 of DOX-GNMs increased by 3.3-fold, 2.0-fold and 2.3-fold compared with DOX-Sol in P-gp over-expressing MCF-7/Adr cells after 24h, 48h and 72h, internalized via macropinocytosis-mediated and clathrin-mediated endocytosis. This study suggests that Gemini-PEG2K-GCDS nanomicelle is a promising long circulating delivery system for anti-tumor drugs via extended blood circulation and improved tumor distribution.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, PR China; Institute of Clinical Pharmacology, Department of Pharmacy, General Hospital of Ningxia Medical University, No. 804 Shengli Street, Yinchuan 750004, PR China.
authors.forename: Wenping
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: sunjin66@21cn.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.affiliation: Key Laboratory of Structure Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, PR China.
authors.forename: Wuhong
authors.initials: W
authors.lastname: Fang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, PR China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Ai
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, PR China.
authors.forename: Cuifang
authors.initials: C
authors.lastname: Cai
authors.affiliation: School of Materials Science and Engineering, Xi'an Jiaotong University, Xi'an 710019, PR China.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, PR China.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Su
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, PR China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, PR China.
authors.forename: Mengying
authors.initials: M
authors.lastname: Tao
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, PR China.
authors.forename: Xiaodan
authors.initials: X
authors.lastname: Yan
authors.affiliation: Key Laboratory of Structure Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, PR China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, PR China. Electronic address: hezhgui_student@aliyun.com.
authors.forename: Zhonggui
authors.initials: Z
authors.lastname: He
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D001692:Biological Transport; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations; D004317:Doxorubicin / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D065546:Drug Liberation; D005989:Glycerides / Q000737:chemistry*; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D015394:Molecular Structure; D049329:Nanostructures / Q000737:chemistry*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D005989:Glycerides; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: Doxorubicin; Nanomicelles; Peglyated distearylglycerol; Tumor delivery; X-shaped four-armed