Cargando…

Modification of translationally controlled tumor protein-derived protein transduction domain for improved intranasal delivery of insulin

Carrier peptides, termed protein transduction domains (PTDs), serve as provide promising vehicles for intranasal delivery of macromolecular drugs. A mutant PTD derived from human translationally controlled tumor protein (TCTP-PTD 13, MIIFRALISHKK) was reported to provide enhanced intranasal delivery...

Descripción completa

Detalles Bibliográficos
Autores principales: Bae, Hae-Duck, Lee, Joohyun, Jun, Kyu-Yeon, Kwon, Youngjoo, Lee, Kyunglim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058520/
https://www.ncbi.nlm.nih.gov/pubmed/29688087
http://dx.doi.org/10.1080/10717544.2018.1464081
_version_ 1783341713384800256
author Bae, Hae-Duck
Lee, Joohyun
Jun, Kyu-Yeon
Kwon, Youngjoo
Lee, Kyunglim
author_facet Bae, Hae-Duck
Lee, Joohyun
Jun, Kyu-Yeon
Kwon, Youngjoo
Lee, Kyunglim
author_sort Bae, Hae-Duck
collection PubMed
description Carrier peptides, termed protein transduction domains (PTDs), serve as provide promising vehicles for intranasal delivery of macromolecular drugs. A mutant PTD derived from human translationally controlled tumor protein (TCTP-PTD 13, MIIFRALISHKK) was reported to provide enhanced intranasal delivery of insulin. In this study, we tested whether its efficiency could be further improved by replacing amino acids in TCTP-PTD 13 or changing the amino acids in the carrier peptides from the l- to the d-form. We assessed the pharmacokinetics of PTD-mediated transmucosal delivery of insulin in normal rats and the activity of insulin in alloxan-induced diabetic rats. The safety/toxicity profile of the carrier peptides was evaluated based on the release of lactate dehydrogenase (LDH) in nasal wash fluid, body weight changes, and several biochemical parameters. Pharmacokinetic and pharmacodynamic studies showed that the l-form of a double substitution A6L, I8A (MIIFRLLASHKK), designated as l-TCTP-PTD 13M2 was the most effective carrier for intranasal insulin delivery. The relative bioavailability of insulin co-administered intranasally with l-TCTP-PTD 13M2 was 37.1% of the value obtained by the subcutaneous route, which was 1.68-fold higher than for insulin co-administered with l-TCTP-PTD 13. Moreover, co-administration of insulin plus l-TCTP-PTD 13M2 reduced blood glucose levels compared to levels in diabetic rats treated with insulin plus l-TCTP-PTD 13. There was no evidence of toxicity. These results suggest that the newly designed PTD is a useful carrier peptide for the intranasal delivery of drugs or biomolecules.
format Online
Article
Text
id pubmed-6058520
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Taylor & Francis
record_format MEDLINE/PubMed
spelling pubmed-60585202018-08-17 Modification of translationally controlled tumor protein-derived protein transduction domain for improved intranasal delivery of insulin Bae, Hae-Duck Lee, Joohyun Jun, Kyu-Yeon Kwon, Youngjoo Lee, Kyunglim Drug Deliv Research Article Carrier peptides, termed protein transduction domains (PTDs), serve as provide promising vehicles for intranasal delivery of macromolecular drugs. A mutant PTD derived from human translationally controlled tumor protein (TCTP-PTD 13, MIIFRALISHKK) was reported to provide enhanced intranasal delivery of insulin. In this study, we tested whether its efficiency could be further improved by replacing amino acids in TCTP-PTD 13 or changing the amino acids in the carrier peptides from the l- to the d-form. We assessed the pharmacokinetics of PTD-mediated transmucosal delivery of insulin in normal rats and the activity of insulin in alloxan-induced diabetic rats. The safety/toxicity profile of the carrier peptides was evaluated based on the release of lactate dehydrogenase (LDH) in nasal wash fluid, body weight changes, and several biochemical parameters. Pharmacokinetic and pharmacodynamic studies showed that the l-form of a double substitution A6L, I8A (MIIFRLLASHKK), designated as l-TCTP-PTD 13M2 was the most effective carrier for intranasal insulin delivery. The relative bioavailability of insulin co-administered intranasally with l-TCTP-PTD 13M2 was 37.1% of the value obtained by the subcutaneous route, which was 1.68-fold higher than for insulin co-administered with l-TCTP-PTD 13. Moreover, co-administration of insulin plus l-TCTP-PTD 13M2 reduced blood glucose levels compared to levels in diabetic rats treated with insulin plus l-TCTP-PTD 13. There was no evidence of toxicity. These results suggest that the newly designed PTD is a useful carrier peptide for the intranasal delivery of drugs or biomolecules. Taylor & Francis 2018-04-24 /pmc/articles/PMC6058520/ /pubmed/29688087 http://dx.doi.org/10.1080/10717544.2018.1464081 Text en © 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Bae, Hae-Duck
Lee, Joohyun
Jun, Kyu-Yeon
Kwon, Youngjoo
Lee, Kyunglim
Modification of translationally controlled tumor protein-derived protein transduction domain for improved intranasal delivery of insulin
title Modification of translationally controlled tumor protein-derived protein transduction domain for improved intranasal delivery of insulin
title_full Modification of translationally controlled tumor protein-derived protein transduction domain for improved intranasal delivery of insulin
title_fullStr Modification of translationally controlled tumor protein-derived protein transduction domain for improved intranasal delivery of insulin
title_full_unstemmed Modification of translationally controlled tumor protein-derived protein transduction domain for improved intranasal delivery of insulin
title_short Modification of translationally controlled tumor protein-derived protein transduction domain for improved intranasal delivery of insulin
title_sort modification of translationally controlled tumor protein-derived protein transduction domain for improved intranasal delivery of insulin
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058520/
https://www.ncbi.nlm.nih.gov/pubmed/29688087
http://dx.doi.org/10.1080/10717544.2018.1464081
work_keys_str_mv AT baehaeduck modificationoftranslationallycontrolledtumorproteinderivedproteintransductiondomainforimprovedintranasaldeliveryofinsulin
AT leejoohyun modificationoftranslationallycontrolledtumorproteinderivedproteintransductiondomainforimprovedintranasaldeliveryofinsulin
AT junkyuyeon modificationoftranslationallycontrolledtumorproteinderivedproteintransductiondomainforimprovedintranasaldeliveryofinsulin
AT kwonyoungjoo modificationoftranslationallycontrolledtumorproteinderivedproteintransductiondomainforimprovedintranasaldeliveryofinsulin
AT leekyunglim modificationoftranslationallycontrolledtumorproteinderivedproteintransductiondomainforimprovedintranasaldeliveryofinsulin