title: Development of novel self-assembled ES-PLGA hybrid nanoparticles for improving oral absorption of doxorubicin hydrochloride by P-gp inhibition: In vitro and in vivo evaluation.
abstract: To increase the encapsulation efficiency and oral absorption of doxorubicin hydrochloride (DOX), a novel drug delivery system of enoxaparin sodium-PLGA hybrid nanoparticles (EPNs) was successfully designed. By introducing the negative polymer of enoxaparin sodium (ES) to form an electrostatic complex with the cationic drug, DOX, the encapsulation efficiency (93.78%) of DOX was significantly improved. The X-ray diffraction (XRD) results revealed that the DOX-ES complex was in an amorphous form. An in vitro release (pH6.8 PBS) study showed the excellent sustained-release characteristics of DOX-loaded EPNs (DOX-EPNs). In addition, in situ intestinal perfusion and intestinal biodistribution experiments demonstrated the improved membrane permeability and intestinal wall bioadhesion of DOX-EPNs, and caveolin- and clathrin-mediated endocytosis pathways were the main mechanisms responsible. The cytotoxicity of DOX was significantly increased by EPNs in Caco-2 cells, compared with DOX-Sol. Confocal laser scanning microscope (CLSM) images confirmed that the amount of DOX-EPNs internalized by Caco-2 cells was higher than that of DOX-Sol showing that P-glycoprotein-mediated drug efflux was reduced by the introduction of EPNs. The qualitative detection of transcytosis demonstrated the ability of the nanoparticles (NPs) to cross Caco-2 cell monolayers. An in vivo toxicity experiment demonstrated that DOX-EPNs reduced cardiac and renal toxic effects and were biocompatible. An in vivo pharmacokinetics study showed that the AUC(0-t)and t1/2of DOX-EPNs were increased to 3.63-fold and 2.47-fold in comparison with DOX solution (DOX-Sol), respectively. All these results indicated that the novel EPNs were an excellent platform to improve the encapsulation efficiency of an aqueous solution of this antitumor drug and its oral bioavailability.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmaceutical Analysis, School of Pharmacy, Shenyang Pharmaceutical University, No. 103Wenhua Road, Shenyang 110016, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Bingjun
authors.initials: B
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China; Municipal Key Laboratory of Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Department of Pharmaceutical Analysis, School of Pharmacy, Shenyang Pharmaceutical University, No. 103Wenhua Road, Shenyang 110016, China. Electronic address: zhangpengspu@163.com.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, 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: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism; D001672:Biocompatible Materials / Q000737:chemistry; D001682:Biological Availability; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry* / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry*; D053758:Nanoparticles / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D014018:Tissue Distribution; D014961:X-Ray Diffraction / Q000379:methods
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D004337:Drug Carriers; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D004317:Doxorubicin
keywords: Doxorubicin hydrochloride; Electrostatic interaction; Enoxaparin sodium; Oral bioavailability; Self-assembled ES-PLGA nanoparticles