title: PEG-derivatized octacosanol as micellar carrier for paclitaxel delivery.
abstract: In this study, PEG-derivatized octacosanol copolymer was successfully developed to improve the anti-tumor activity and eliminate toxicity of the commercial formulation of paclitaxel (PTX). MPEG2K-C28, the conjugation of monomethoxy Poly(ethylene glycol) 2000 and octacosanol, was readily soluble in aqueous solution and self-assembled to form micelles with small sizes (< 20 nm) that are efficient in encapsulating PTX with a drug loading of 9.38 ± 0.18% and an encapsulation efficiency of 93.90 ± 2.12%. Meanwhile, octacosanol is very safe for humans and amazingly exhibits antitumor activity through inhibition activity of matrix metalloproteinases (MMPs) and translocation of the transcription factor (nuclear factor-kappa B, NF-κB) to the nucleus, which may be able to promote synergistic effects with PTX. A sustained and slower in vitro release behavior was observed in the (PTX micelles) than that of Taxol. PTX micelles exhibited more potent cytotoxicity than Taxol in the 4T1 breast cancer cell line. More interestingly, MPEG2K-C28 selectively inhibited the growth of 4T1 cells rather than the normal cells (HEK293 and L929 cell lines), indicating the antitumor activity of octacosanol remained after conjugation with MPEG. Acute toxicity evaluations indicated that MPEG2K-C28 was a safe drug carrier. Pharmacokinetic study revealed that PTX micelles improved the T1/2 and AUC of PTX (compared with Taxol) from 1.910 ± 0.139 h and 13.999 ± 1.109 mg/l × h to 2.876 ± 0.532 h and 76.462 ± 8.619 mg/l × h in vivo, respectively. The maximal tolerated dose (MTD) for PTX micelles (ca. 120 mg PTX/kg) in mice was significantly higher than that for Taxol (ca. 20mg PTX/kg). PTX micelles exhibited slightly better antitumor activity than Taxol but safer in 4T1 breast cancer model in vivo. The cell apoptosis in the immunofluorescent studies and the cell proliferation in the immunohistochemical studies also proved the results. In conclusion, MPEG2K-C28 is a simple, safe and effective drug delivery carrier for PTX, and has some therapeutic effects in 4T1 cells in vitro. PTX micelles showed significant antitumor activity in vivo with low systemic toxicity in 4T1 breast cancer. MPEG2K-C28 micelles entrapping PTX deserve more studies in the future.
authors.affiliation: Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Road, Wenzhou 325027, PR China; R&D Center of New Product, Guangdong Zhongsheng Pharmaceutical Co.,Ltd., Dongguan 523325,PR China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, PR China.
authors.forename: Bingyang
authors.initials: B
authors.lastname: Chu
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Qu
authors.affiliation: Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Road, Wenzhou 325027, PR China.
authors.forename: Yixing
authors.initials: Y
authors.lastname: Huang
authors.affiliation: R&D Center of New Product, Guangdong Zhongsheng Pharmaceutical Co.,Ltd., Dongguan 523325,PR China.
authors.forename: Lan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: R&D Center of New Product, Guangdong Zhongsheng Pharmaceutical Co.,Ltd., Dongguan 523325,PR China.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Chen
authors.affiliation: R&D Center of New Product, Guangdong Zhongsheng Pharmaceutical Co.,Ltd., Dongguan 523325,PR China.
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Long
authors.affiliation: College of Chemistry, Sichuan University, Chengdu 610065, PR China.
authors.forename: Yunqi
authors.initials: Y
authors.lastname: He
authors.affiliation: Key Laboratory of Construction and Detection of Guangdong Province, Southern Medical University, Guangzhou 510515, PR China. Electronic address: 1284572007@qq.com.
authors.forename: Caiwen
authors.initials: C
authors.lastname: Ou
authors.affiliation: Department of Orthopaedic Surgery, Second Affiliated Hospital of Wenzhou Medical University, 109 Xueyuan Road, Wenzhou 325027, PR China; R&D Center of New Product, Guangdong Zhongsheng Pharmaceutical Co.,Ltd., Dongguan 523325,PR China; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, PR China. Electronic address: anderson-qian@163.com.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Qian
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D065546:Drug Liberation; D005233:Fatty Alcohols / Q000737:chemistry; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008807:Mice, Inbred BALB C; D008823:Micelles; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D003374:Coumarins; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005233:Fatty Alcohols; D008823:Micelles; D013844:Thiazoles; C517282:coumarin 6; D011092:Polyethylene Glycols; C044309:1-octacosanol; D017239:Paclitaxel
keywords: Cancer therapy; Drug delivery; Micelles; Octacosanol; Paclitaxel