Cargando…

Thermoresponsive Copolymer Nanovectors Improve the Bioavailability of Retrograde Inhibitors in the Treatment of Leishmania Infections

Clinical manifestations of leishmaniasis range from self-healing, cutaneous lesions to fatal infections of the viscera. With no preventative Leishmania vaccine available, the frontline option against leishmaniasis is chemotherapy. Unfortunately, currently available anti-Leishmania drugs face several...

Descripción completa

Detalles Bibliográficos
Autores principales: Craig, Evan, Calarco, Anna, Conte, Raffaele, Ambrogi, Veronica, d’Ayala, Giovanna Gomez, Alabi, Philip, Sello, Jason K., Cerruti, Pierfrancesco, Kima, Peter E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417477/
https://www.ncbi.nlm.nih.gov/pubmed/34490142
http://dx.doi.org/10.3389/fcimb.2021.702676
_version_ 1783748389567987712
author Craig, Evan
Calarco, Anna
Conte, Raffaele
Ambrogi, Veronica
d’Ayala, Giovanna Gomez
Alabi, Philip
Sello, Jason K.
Cerruti, Pierfrancesco
Kima, Peter E.
author_facet Craig, Evan
Calarco, Anna
Conte, Raffaele
Ambrogi, Veronica
d’Ayala, Giovanna Gomez
Alabi, Philip
Sello, Jason K.
Cerruti, Pierfrancesco
Kima, Peter E.
author_sort Craig, Evan
collection PubMed
description Clinical manifestations of leishmaniasis range from self-healing, cutaneous lesions to fatal infections of the viscera. With no preventative Leishmania vaccine available, the frontline option against leishmaniasis is chemotherapy. Unfortunately, currently available anti-Leishmania drugs face several obstacles, including toxicity that limits dosing and emergent drug resistant strains in endemic regions. It is, therefore, imperative that more effective drug formulations with decreased toxicity profiles are developed. Previous studies had shown that 2-(((5-Methyl-2-thienyl)methylene)amino)-N-phenylbenzamide (also called Retro-2) has efficacy against Leishmania infections. Structure–activity relationship (SAR) analogs of Retro-2, using the dihydroquinazolinone (DHQZ) base structure, were subsequently described that are more efficacious than Retro-2. However, considering the hydrophobic nature of these compounds that limits their solubility and uptake, the current studies were initiated to determine whether the solubility of Retro-2 and its SAR analogs could be enhanced through encapsulation in amphiphilic polymer nanoparticles. We evaluated encapsulation of these compounds in the amphiphilic, thermoresponsive oligo(ethylene glycol) methacrylate-co-pentafluorostyrene (PFG30) copolymer that forms nanoparticle aggregates upon heating past temperatures of 30°C. The hydrophobic tracer, coumarin 6, was used to evaluate uptake of a hydrophobic molecule into PFG30 aggregates. Mass spectrometry analysis showed considerably greater delivery of encapsulated DHQZ analogs into infected cells and more rapid shrinkage of L. amazonensis communal vacuoles. Moreover, encapsulation in PFG30 augmented the efficacy of Retro-2 and its SAR analogs to clear both L. amazonensis and L. donovani infections. These studies demonstrate that encapsulation of compounds in PFG30 is a viable approach to dramatically increase bioavailability and efficacy of anti-Leishmania compounds.
format Online
Article
Text
id pubmed-8417477
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-84174772021-09-05 Thermoresponsive Copolymer Nanovectors Improve the Bioavailability of Retrograde Inhibitors in the Treatment of Leishmania Infections Craig, Evan Calarco, Anna Conte, Raffaele Ambrogi, Veronica d’Ayala, Giovanna Gomez Alabi, Philip Sello, Jason K. Cerruti, Pierfrancesco Kima, Peter E. Front Cell Infect Microbiol Cellular and Infection Microbiology Clinical manifestations of leishmaniasis range from self-healing, cutaneous lesions to fatal infections of the viscera. With no preventative Leishmania vaccine available, the frontline option against leishmaniasis is chemotherapy. Unfortunately, currently available anti-Leishmania drugs face several obstacles, including toxicity that limits dosing and emergent drug resistant strains in endemic regions. It is, therefore, imperative that more effective drug formulations with decreased toxicity profiles are developed. Previous studies had shown that 2-(((5-Methyl-2-thienyl)methylene)amino)-N-phenylbenzamide (also called Retro-2) has efficacy against Leishmania infections. Structure–activity relationship (SAR) analogs of Retro-2, using the dihydroquinazolinone (DHQZ) base structure, were subsequently described that are more efficacious than Retro-2. However, considering the hydrophobic nature of these compounds that limits their solubility and uptake, the current studies were initiated to determine whether the solubility of Retro-2 and its SAR analogs could be enhanced through encapsulation in amphiphilic polymer nanoparticles. We evaluated encapsulation of these compounds in the amphiphilic, thermoresponsive oligo(ethylene glycol) methacrylate-co-pentafluorostyrene (PFG30) copolymer that forms nanoparticle aggregates upon heating past temperatures of 30°C. The hydrophobic tracer, coumarin 6, was used to evaluate uptake of a hydrophobic molecule into PFG30 aggregates. Mass spectrometry analysis showed considerably greater delivery of encapsulated DHQZ analogs into infected cells and more rapid shrinkage of L. amazonensis communal vacuoles. Moreover, encapsulation in PFG30 augmented the efficacy of Retro-2 and its SAR analogs to clear both L. amazonensis and L. donovani infections. These studies demonstrate that encapsulation of compounds in PFG30 is a viable approach to dramatically increase bioavailability and efficacy of anti-Leishmania compounds. Frontiers Media S.A. 2021-08-19 /pmc/articles/PMC8417477/ /pubmed/34490142 http://dx.doi.org/10.3389/fcimb.2021.702676 Text en Copyright © 2021 Craig, Calarco, Conte, Ambrogi, d’Ayala, Alabi, Sello, Cerruti and Kima https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular and Infection Microbiology
Craig, Evan
Calarco, Anna
Conte, Raffaele
Ambrogi, Veronica
d’Ayala, Giovanna Gomez
Alabi, Philip
Sello, Jason K.
Cerruti, Pierfrancesco
Kima, Peter E.
Thermoresponsive Copolymer Nanovectors Improve the Bioavailability of Retrograde Inhibitors in the Treatment of Leishmania Infections
title Thermoresponsive Copolymer Nanovectors Improve the Bioavailability of Retrograde Inhibitors in the Treatment of Leishmania Infections
title_full Thermoresponsive Copolymer Nanovectors Improve the Bioavailability of Retrograde Inhibitors in the Treatment of Leishmania Infections
title_fullStr Thermoresponsive Copolymer Nanovectors Improve the Bioavailability of Retrograde Inhibitors in the Treatment of Leishmania Infections
title_full_unstemmed Thermoresponsive Copolymer Nanovectors Improve the Bioavailability of Retrograde Inhibitors in the Treatment of Leishmania Infections
title_short Thermoresponsive Copolymer Nanovectors Improve the Bioavailability of Retrograde Inhibitors in the Treatment of Leishmania Infections
title_sort thermoresponsive copolymer nanovectors improve the bioavailability of retrograde inhibitors in the treatment of leishmania infections
topic Cellular and Infection Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417477/
https://www.ncbi.nlm.nih.gov/pubmed/34490142
http://dx.doi.org/10.3389/fcimb.2021.702676
work_keys_str_mv AT craigevan thermoresponsivecopolymernanovectorsimprovethebioavailabilityofretrogradeinhibitorsinthetreatmentofleishmaniainfections
AT calarcoanna thermoresponsivecopolymernanovectorsimprovethebioavailabilityofretrogradeinhibitorsinthetreatmentofleishmaniainfections
AT conteraffaele thermoresponsivecopolymernanovectorsimprovethebioavailabilityofretrogradeinhibitorsinthetreatmentofleishmaniainfections
AT ambrogiveronica thermoresponsivecopolymernanovectorsimprovethebioavailabilityofretrogradeinhibitorsinthetreatmentofleishmaniainfections
AT dayalagiovannagomez thermoresponsivecopolymernanovectorsimprovethebioavailabilityofretrogradeinhibitorsinthetreatmentofleishmaniainfections
AT alabiphilip thermoresponsivecopolymernanovectorsimprovethebioavailabilityofretrogradeinhibitorsinthetreatmentofleishmaniainfections
AT sellojasonk thermoresponsivecopolymernanovectorsimprovethebioavailabilityofretrogradeinhibitorsinthetreatmentofleishmaniainfections
AT cerrutipierfrancesco thermoresponsivecopolymernanovectorsimprovethebioavailabilityofretrogradeinhibitorsinthetreatmentofleishmaniainfections
AT kimapetere thermoresponsivecopolymernanovectorsimprovethebioavailabilityofretrogradeinhibitorsinthetreatmentofleishmaniainfections