title: Synthetic high-density lipoproteins for delivery of 10-hydroxycamptothecin.
abstract: The purpose of this study was to develop a novel synthetic high-density lipoprotein (sHDL) nanoparticle delivery system for 10-hydroxycamptothecin (HCPT) for treatment of colon carcinoma. HDL is recognized by scavenger receptor B-I (SR-BI) over-expressed in colon carcinomas 5- to 35-fold relative to the human fibroblasts. The sHDL nanoparticles were composed of apolipoprotein A-I mimic peptide (5A) and contained 0.5%-1.5% (w/w) of HCPT. An optimized HCPT-sHDL formulation exhibited 0.7% HCPT loading with 70% efficiency with an average size of 10-12 nm. Partitioning of HCPT in the sHDL lipid membrane enhanced drug stability in its active lactone form, increased solubilization, and enabled slow release. Cytotoxicity studies in HT29 colon carcinoma cells revealed that the IC50of HCPT-sHDL was approximately 3-fold lower than that of free HCPT. Pharmacokinetics in rats following intravenous administration showed that the area under the serum concentration-time curve (AUC0-t) and Cmaxof HCPT-HDL were 2.7- and 6.5-fold higher relative to the values for the free HCPT, respectively. These results suggest that sHDL-based formulations of hydrophobic drugs are useful for future evaluation in treatment of SR-BI-positive tumors.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China; Department of Pharmaceutical Sciences, Biointerfaces Institute, College of Pharmacy, University of Michigan.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wen
authors.affiliation: Department of Pharmaceutical Sciences, Biointerfaces Institute, College of Pharmacy, University of Michigan.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People's Republic of China.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Kan
authors.affiliation: Department of Pharmaceutical Sciences, Biointerfaces Institute, College of Pharmacy, University of Michigan.
authors.forename: Rose
authors.initials: R
authors.lastname: Ackermann
authors.affiliation: Department of Pharmaceutical Sciences, Biointerfaces Institute, College of Pharmacy, University of Michigan.
authors.forename: Karl
authors.initials: K
authors.lastname: Olsen
authors.affiliation: Department of Pharmaceutical Sciences, Biointerfaces Institute, College of Pharmacy, University of Michigan.
authors.forename: Anna
authors.initials: A
authors.lastname: Schwendeman
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D016632:Apolipoprotein A-I / Q000737:chemistry; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D004355:Drug Stability; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000008:administration & dosage / Q000737:chemistry*; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry* / Q000633:toxicity; D017207:Rats, Sprague-Dawley
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016632:Apolipoprotein A-I; D007783:Lactones; D008075:Lipoproteins, HDL; C028098:10-hydroxycamptothecin; D002166:Camptothecin
keywords: SR-BI receptor; apolipoprotein A-I mimic peptide; camptothecin; colon carcinoma; nanodisc; nanoparticle; phospholipids