title: Core-matched encapsulation of an oleate prodrug into nanostructured lipid carriers with high drug loading capability to facilitate the oral delivery of docetaxel.
abstract: Nanostructured lipid carriers (NLC) have been considered as promising vehicles for oral delivery of taxanes, such as docetaxel (DTX). However, the low drug loading capability (∼5%, w/w) has greatly limited their clinical application. In response to this challenge, a novel lipophilic oleate prodrug of DTX (DTX-OA) was synthesized and efficiently encapsulated in NLC using core-match technology, in which liquid lipid (OA) was used as core matrix to enhance compatibility with DTX-OA. DTX-OA-NLC showed uniform particle size of about 100nm with markedly high drug loading capability (∼23% of DTX, w/w) compared with DTX-NLC (∼5%, w/w). Besides, DTX-OA-NLC showed better colloidal stability and slower drug release property compared with DTX-NLC. The prepared NLC could be accumulated more easily in MDCK cells than drug solution, and clathrin-mediated endocytosis was the main endocytosis pathway. In situ single-pass intestinal perfusion (SPIP) and intestinal biodistribution studies demonstrated the improved membrane permeability and intestinal wall bioadhesion of NLCs. The bioavailability of DTX-OA-NLC showed 4.04-fold and 2.06-fold higher than DTX solution and DTX-NLC, respectively. These results suggest that the core-matched prodrug-NLC is a promising platform to facilitate the oral delivery of DTX.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.
authors.forename: Bingjun
authors.initials: B
authors.lastname: Sun
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Luo
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.
authors.forename: Menglin
authors.initials: M
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Du
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.
authors.forename: Donghua
authors.initials: D
authors.lastname: Di
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.
authors.forename: Guolian
authors.initials: G
authors.lastname: Ren
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23220, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Pan
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Fu
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China; Municipal Key Laboratory of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China. Electronic address: sunjin66@21cn.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang 110016, China. Electronic address: hezhonggui@vip.163.com.
authors.forename: Zhonggui
authors.initials: Z
authors.lastname: He
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D001682:Biological Availability; D001692:Biological Transport; D000077143:Docetaxel; D004285:Dogs; D004337:Drug Carriers; D004339:Drug Compounding / Q000379:methods; D004705:Endocytosis / Q000502:physiology; D005989:Glycerides / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D007408:Intestinal Absorption / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D061985:Madin Darby Canine Kidney Cells; D049329:Nanostructures / Q000737:chemistry*; D009829:Oleic Acids / Q000737:chemistry; D010316:Particle Size; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043823:Taxoids / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014810:Vitamin E / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D005989:Glycerides; D009829:Oleic Acids; D011355:Prodrugs; D043823:Taxoids; D014810:Vitamin E; D000077143:Docetaxel; C014225:tocophersolan
keywords: Core-match; Docetaxel; Lipophilic prodrug; Nanostructured lipid carriers; Oral delivery