title: On employing a translationally controlled tumor protein-derived protein transduction domain analog for transmucosal delivery of drugs.
abstract: Protein transduction domains (PTDs) are recognized as promising vehicles for the delivery of macromolecular drugs. We have previously shown that a region in the N-terminus (residues 1-10) of translationally controlled tumor protein (TCTP) contains a PTD (TCTP-PTD), MIIYRDLISH, which can serve as a vehicle for the delivery of macromolecules into the cells and tissues. In the current study, we evaluated the potential and safety of TCTP-PTD and its three mutant analogs as nasal absorption enhancers for delivery of drugs. We conducted this evaluation employing insulin as test drug. We examined the degree to which insulin was absorbed in nasal mucosa and also if any mucosal damage occurs following such nasal delivery of insulin using TCTP-PTDs as a vehicle. The systemic delivery of insulin was assessed by measuring the changes in blood glucose levels after nasal coadministration insulin and four PTDs. Of the three TCTP-PTD analogs examined, one, TCTP-PTD analog (MIIFRALISHKK) significantly enhanced the nasal absorption of insulin in both normal and streptozotocin-induced diabetic mice. The relative pharmacological bioavailability of insulin nasally coadministered with the TCTP-PTD analog was 21.3% relative to the subcutaneous route. Molecular association between insulin and the TCTP-PTD analog was observed by fluorescence resonance energy transfer measurements. The binding between the TCTP-PTD analog and insulin may enable the penetration of insulin through the nasal mucosa. Histological examination of mice nasal mucosa 7 days after repeated nasal administration showed no evidence of toxicity at the site of nasal administration. In this study using insulin as a test system we demonstrate that the TCTP-PTD analog offers a promising approach for nasal peptides and protein-drugs delivery.
authors.affiliation: College of Pharmacy, Center for Cell Signaling and Drug Discovery Research, Ewha Womans University, Seoul, Republic of Korea.
authors.forename: Hae-duck
authors.initials: HD
authors.lastname: Bae
authors.forename: Kyunglim
authors.initials: K
authors.lastname: Lee
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D014408:Biomarkers, Tumor / Q000737:chemistry*; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000378:metabolism; D016503:Drug Delivery Systems; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009297:Nasal Mucosa / Q000378:metabolism*; D009842:Oligopeptides / Q000008:administration & dosage*; D017434:Protein Structure, Tertiary; D014161:Transduction, Genetic; D000090324:Tumor Protein, Translationally-Controlled 1
chemical_list: D014408:Biomarkers, Tumor; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D009842:Oligopeptides; C000715648:Tpt1 protein, mouse; D000090324:Tumor Protein, Translationally-Controlled 1
keywords: Insulin; Nasal absorption; Protein transduction domain (PTD); TCTP-PTD; Translationally controlled tumor protein (TCTP)