title: Reversible lipidization of somatostatin analogues for the liver targeting.
abstract: Tyr(3)-octreotide (TOC), a somatostatin analogue, is reversibly lipidized for passive delivery to the liver with the aim of increasing its association with hepatocytes. The reversibly lipidized TOC (REAL-TOC) was formed by the conjugation of the N-palmitoyl cysteinyl moiety to the cysteinyl residues of reduced TOC through disulfide linkages and characterized by matrix-assisted laser desorption/ionization (MALDI)-time of flight (TOF) analysis. The measured mass of REAL-TOC (M+H)(+) is 1752.31 Da (calculated mass: 1752.78), confirming that two molecules of N-palmitoyl cysteines are linked to TOC via disulfide bonds. TOC and REAL-TOC were radioiodinated and administered to mice. Their biodistribution and intrahepatic distribution were subsequently investigated. The area under the curve (AUC) of (125)I-REAL-TOC in the liver was 3.8-fold greater than that of (125)I-TOC, with 20.5% and 5.8% of the injected dose (ID)/g of (125)I-REAL-TOC remaining in the liver at 2 and 24h post injection, respectively. Within the liver, TOC was primarily distributed to parenchymal cells (PC). Nevertheless, TOC was quickly excreted out and only 2.4% ID per 100mg protein remained in the PC at 2h post injection. (125)I-REAL-TOC was retained in PC for up to 2h with a constant concentration of around 6% ID/100mg protein. (125)I-REAL-TOC was also highly associated with nonparenchymal cells (NPC) at significantly higher levels than (125)I-TOC at 10min, 1h and 2h post injection. Since somatostatin analogues have been evaluated for treating late-stage hepatocellular carcinoma (HCC), the reversibly lipidized conjugates may possess enhanced therapeutic efficacy due to the liver-targeting effect.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA 90089, USA.
authors.forename: Liyun
authors.initials: L
authors.lastname: Yuan
authors.forename: Jeff
authors.initials: J
authors.lastname: Wang
authors.forename: Wei-Chiang
authors.initials: WC
authors.lastname: Shen
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D015282:Octreotide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D019308:Palmitic Acid / Q000737:chemistry*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014018:Tissue Distribution
chemical_list: C045210:3-Tyr-octreotide; D019308:Palmitic Acid; D015282:Octreotide