title: Curcumin-carboxymethyl chitosan (CNC) conjugate and CNC/LHR mixed polymeric micelles as new approaches to improve the oral absorption of P-gp substrate drugs.
abstract: The low oral bioavailability of numerous drugs has been mostly attributed to the significant effect of P-gp-mediated efflux on intestinal drug transport. Herein, we developed mixed polymeric micelles (MPMs) comprised of curcumin-carboxymethyl chitosan (CNC) conjugate, as a potential inhibitor of P-gp-mediated efflux and gastrointestinal absorption enhancer, and low-molecular-weight heparin-all-trans-retinoid acid (LHR) conjugate, as loading material, with the aim to improve the oral absorption of P-gp substrate drugs. CNC conjugate was synthesized by chemical bonding of curcumin (Cur) and carboxymethyl chitosan (CMCS) taking advantage of the inhibition of intestinal P-gp-mediated secretion by Cur and the intestinal absorption enhancement by CMCS. The chemical structure of CNC conjugate was characterized by1H NMR with a degree of substitution of Cur of 4.52-10.20%. More importantly, CNC conjugate markedly improved the stability of Cur in physiological pH. Cyclosporine A-loaded CNC/LHR MPMs (CsA-CNC/LHR MPMs) were prepared by dialysis method, with high drug loading 25.45% and nanoscaled particle size (∼200 nm). In situ single-pass perfusion studies in rats showed that both CsA + CNC mixture and CsA-CNC/LHR MPMs achieved significantly higher Kaand Peffthan CsA suspension in the duodenum and jejunum segments (p <  0.01), which was comparable to verapamil coperfusion effect. Similarly, CsA + CNC mixture and CsA-CNC/LHR MPMs significantly increased the oral bioavailability of CsA as compared to CsA suspension. These results suggest that CNC conjugate might be considered as a promising gastrointestinal absorption enhancer, while CNC/LHR MPMs had the potential to improve the oral absorption of P-gp substrate drugs.
authors.affiliation: a State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing , Jiangsu , China and.
authors.forename: Jiang
authors.initials: J
authors.lastname: Ni
authors.affiliation: a State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing , Jiangsu , China and.
authors.forename: Fengchun
authors.initials: F
authors.lastname: Tian
authors.affiliation: a State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing , Jiangsu , China and.
authors.forename: Fatima Zohra
authors.initials: FZ
authors.lastname: Dahmani
authors.affiliation: a State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing , Jiangsu , China and.
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.affiliation: b Shandong Dyne Marine Biopharmaceutical Co, Ltd , Beijing , China.
authors.forename: Deren
authors.initials: D
authors.lastname: Yue
authors.affiliation: b Shandong Dyne Marine Biopharmaceutical Co, Ltd , Beijing , China.
authors.forename: Shuwang
authors.initials: S
authors.lastname: He
authors.affiliation: a State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing , Jiangsu , China and.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhou
authors.affiliation: a State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University , Nanjing , Jiangsu , China and.
authors.forename: Jing
authors.initials: J
authors.lastname: Yao
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D048271:Chitosan / Q000031:analogs & derivatives* / Q000737:chemistry; D003474:Curcumin / Q000737:chemistry* / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry; D006495:Heparin, Low-Molecular-Weight / Q000737:chemistry*; D007408:Intestinal Absorption / Q000502:physiology; D008297:Male; D008823:Micelles; D010316:Particle Size; D011108:Polymers / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004337:Drug Carriers; D006495:Heparin, Low-Molecular-Weight; D008823:Micelles; D011108:Polymers; C514968:carboxymethyl-chitosan; D048271:Chitosan; D003474:Curcumin
keywords: Carboxymethyl chitosan; P-glycoprotein; curcumin; mixed polymeric micelles; oral absorption enhancer