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A Reversibly Thermoresponsive, Theranostic Nanoemulgel for Tacrolimus Delivery to Activated Macrophages: Formulation and In Vitro Validation

Despite long-term immunosuppression, organ transplant recipients face the risk of immune rejection and graft loss. Tacrolimus (TAC, FK506, Prograf(®)) is an FDA-approved keystone immunosuppressant for preventing transplant rejection. However, it undergoes extensive first-pass metabolism and has a na...

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Autores principales: Vichare, Riddhi, Crelli, Caitlin, Liu, Lu, Das, Amit Chandra, McCallin, Rebecca, Zor, Fatih, Kulahci, Yalcin, Gorantla, Vijay S., Janjic, Jelena M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10610217/
https://www.ncbi.nlm.nih.gov/pubmed/37896130
http://dx.doi.org/10.3390/pharmaceutics15102372
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author Vichare, Riddhi
Crelli, Caitlin
Liu, Lu
Das, Amit Chandra
McCallin, Rebecca
Zor, Fatih
Kulahci, Yalcin
Gorantla, Vijay S.
Janjic, Jelena M.
author_facet Vichare, Riddhi
Crelli, Caitlin
Liu, Lu
Das, Amit Chandra
McCallin, Rebecca
Zor, Fatih
Kulahci, Yalcin
Gorantla, Vijay S.
Janjic, Jelena M.
author_sort Vichare, Riddhi
collection PubMed
description Despite long-term immunosuppression, organ transplant recipients face the risk of immune rejection and graft loss. Tacrolimus (TAC, FK506, Prograf(®)) is an FDA-approved keystone immunosuppressant for preventing transplant rejection. However, it undergoes extensive first-pass metabolism and has a narrow therapeutic window, which leads to erratic bioavailability and toxicity. Local delivery of TAC directly into the graft, instead of systemic delivery, can improve safety, efficacy, and tolerability. Macrophages have emerged as promising therapeutic targets as their increased levels correlate with an increased risk of organ rejection and a poor prognosis post-transplantation. Here, we present a locally injectable drug delivery platform for macrophages, where TAC is incorporated into a colloidally stable nanoemulsion and then formulated as a reversibly thermoresponsive, pluronic-based nanoemulgel (NEG). This novel formulation is designed to undergo a sol-to-gel transition at physiological temperature to sustain TAC release in situ at the site of local application. We also show that TAC-NEG mitigates the release of proinflammatory cytokines and nitric oxide from lipopolysaccharide (LPS)-activated macrophages. To the best of our knowledge, this is the first TAC-loaded nanoemulgel with demonstrated anti-inflammatory effects on macrophages in vitro.
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spelling pubmed-106102172023-10-28 A Reversibly Thermoresponsive, Theranostic Nanoemulgel for Tacrolimus Delivery to Activated Macrophages: Formulation and In Vitro Validation Vichare, Riddhi Crelli, Caitlin Liu, Lu Das, Amit Chandra McCallin, Rebecca Zor, Fatih Kulahci, Yalcin Gorantla, Vijay S. Janjic, Jelena M. Pharmaceutics Article Despite long-term immunosuppression, organ transplant recipients face the risk of immune rejection and graft loss. Tacrolimus (TAC, FK506, Prograf(®)) is an FDA-approved keystone immunosuppressant for preventing transplant rejection. However, it undergoes extensive first-pass metabolism and has a narrow therapeutic window, which leads to erratic bioavailability and toxicity. Local delivery of TAC directly into the graft, instead of systemic delivery, can improve safety, efficacy, and tolerability. Macrophages have emerged as promising therapeutic targets as their increased levels correlate with an increased risk of organ rejection and a poor prognosis post-transplantation. Here, we present a locally injectable drug delivery platform for macrophages, where TAC is incorporated into a colloidally stable nanoemulsion and then formulated as a reversibly thermoresponsive, pluronic-based nanoemulgel (NEG). This novel formulation is designed to undergo a sol-to-gel transition at physiological temperature to sustain TAC release in situ at the site of local application. We also show that TAC-NEG mitigates the release of proinflammatory cytokines and nitric oxide from lipopolysaccharide (LPS)-activated macrophages. To the best of our knowledge, this is the first TAC-loaded nanoemulgel with demonstrated anti-inflammatory effects on macrophages in vitro. MDPI 2023-09-22 /pmc/articles/PMC10610217/ /pubmed/37896130 http://dx.doi.org/10.3390/pharmaceutics15102372 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Vichare, Riddhi
Crelli, Caitlin
Liu, Lu
Das, Amit Chandra
McCallin, Rebecca
Zor, Fatih
Kulahci, Yalcin
Gorantla, Vijay S.
Janjic, Jelena M.
A Reversibly Thermoresponsive, Theranostic Nanoemulgel for Tacrolimus Delivery to Activated Macrophages: Formulation and In Vitro Validation
title A Reversibly Thermoresponsive, Theranostic Nanoemulgel for Tacrolimus Delivery to Activated Macrophages: Formulation and In Vitro Validation
title_full A Reversibly Thermoresponsive, Theranostic Nanoemulgel for Tacrolimus Delivery to Activated Macrophages: Formulation and In Vitro Validation
title_fullStr A Reversibly Thermoresponsive, Theranostic Nanoemulgel for Tacrolimus Delivery to Activated Macrophages: Formulation and In Vitro Validation
title_full_unstemmed A Reversibly Thermoresponsive, Theranostic Nanoemulgel for Tacrolimus Delivery to Activated Macrophages: Formulation and In Vitro Validation
title_short A Reversibly Thermoresponsive, Theranostic Nanoemulgel for Tacrolimus Delivery to Activated Macrophages: Formulation and In Vitro Validation
title_sort reversibly thermoresponsive, theranostic nanoemulgel for tacrolimus delivery to activated macrophages: formulation and in vitro validation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10610217/
https://www.ncbi.nlm.nih.gov/pubmed/37896130
http://dx.doi.org/10.3390/pharmaceutics15102372
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