Modulating cellular autophagy for controlled antiretroviral drug release

Midhun B. Thomas; Divya Prakash Gnanadhas; Prasanta K. Dash; Jatin Machhi; Zhiyi Lin; Joellyn McMillan; Benson Edagwa; Harris Gelbard; Howard E. Gendelman; Santhi Gorantla

doi:10.2217/nnm-2018-0224

Modulating cellular autophagy for controlled antiretroviral drug release

Midhun B. Thomas, Divya Prakash Gnanadhas, Prasanta K. Dash, Jatin Machhi, Zhiyi Lin, Joellyn McMillan, Benson Edagwa, Harris Gelbard, Howard E. Gendelman, Santhi Gorantla

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

Aim: Pharmacologic agents that affect autophagy were tested for their abilities to enhance macrophage nanoformulated antiretroviral drug (ARV) depots and its slow release. Methods: These agents included URMC-099, rapamycin, metformin, desmethylclomipramine, 2-hydroxy-β-cyclodextrin (HBC) and clonidine. Each was administered with nanoformulated atazanavir (ATV) nanoparticles to human monocyte-derived macrophages. ARV retention, antiretroviral activity and nanocrystal autophagosomal formation were evaluated. Results: URMC-099, HBC and clonidine retained ATV. HBC, URMC-099 and rapamycin improved intracellular ATV retention. URMC-099 proved superior among the group in affecting antiretroviral activities. Conclusion: Autophagy inducing agents, notably URMC-099, facilitate nanoformulated ARV depots and lead to sustained release and improved antiretroviral responses. As such, they may be considered for development as part of long acting antiretroviral treatment regimens.

Original language	English (US)
Pages (from-to)	2139-2154
Number of pages	16
Journal	Nanomedicine
Volume	13
Issue number	17
DOIs	https://doi.org/10.2217/nnm-2018-0224
State	Published - Sep 1 2018

Keywords

2-hydroxy-β-cyclodextrin (HBC)
URMC-099
autophagy
clonidine
desmethylclomipramine (DMC)
long acting slow effective release antiretroviral therapy
metformin
monocyte-derived macrophages
rapamycin

ASJC Scopus subject areas

Bioengineering
Development
Biomedical Engineering
General Materials Science
Medicine (miscellaneous)

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title = "Modulating cellular autophagy for controlled antiretroviral drug release",

abstract = "Aim: Pharmacologic agents that affect autophagy were tested for their abilities to enhance macrophage nanoformulated antiretroviral drug (ARV) depots and its slow release. Methods: These agents included URMC-099, rapamycin, metformin, desmethylclomipramine, 2-hydroxy-β-cyclodextrin (HBC) and clonidine. Each was administered with nanoformulated atazanavir (ATV) nanoparticles to human monocyte-derived macrophages. ARV retention, antiretroviral activity and nanocrystal autophagosomal formation were evaluated. Results: URMC-099, HBC and clonidine retained ATV. HBC, URMC-099 and rapamycin improved intracellular ATV retention. URMC-099 proved superior among the group in affecting antiretroviral activities. Conclusion: Autophagy inducing agents, notably URMC-099, facilitate nanoformulated ARV depots and lead to sustained release and improved antiretroviral responses. As such, they may be considered for development as part of long acting antiretroviral treatment regimens.",

keywords = "2-hydroxy-β-cyclodextrin (HBC), URMC-099, autophagy, clonidine, desmethylclomipramine (DMC), long acting slow effective release antiretroviral therapy, metformin, monocyte-derived macrophages, rapamycin",

author = "Thomas, {Midhun B.} and Gnanadhas, {Divya Prakash} and Dash, {Prasanta K.} and Jatin Machhi and Zhiyi Lin and Joellyn McMillan and Benson Edagwa and Harris Gelbard and Gendelman, {Howard E.} and Santhi Gorantla",

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language = "English (US)",

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AU - Thomas, Midhun B.

AU - Gnanadhas, Divya Prakash

AU - Dash, Prasanta K.

AU - Machhi, Jatin

AU - Lin, Zhiyi

AU - McMillan, Joellyn

AU - Edagwa, Benson

AU - Gelbard, Harris

AU - Gendelman, Howard E.

AU - Gorantla, Santhi

PY - 2018/9/1

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N2 - Aim: Pharmacologic agents that affect autophagy were tested for their abilities to enhance macrophage nanoformulated antiretroviral drug (ARV) depots and its slow release. Methods: These agents included URMC-099, rapamycin, metformin, desmethylclomipramine, 2-hydroxy-β-cyclodextrin (HBC) and clonidine. Each was administered with nanoformulated atazanavir (ATV) nanoparticles to human monocyte-derived macrophages. ARV retention, antiretroviral activity and nanocrystal autophagosomal formation were evaluated. Results: URMC-099, HBC and clonidine retained ATV. HBC, URMC-099 and rapamycin improved intracellular ATV retention. URMC-099 proved superior among the group in affecting antiretroviral activities. Conclusion: Autophagy inducing agents, notably URMC-099, facilitate nanoformulated ARV depots and lead to sustained release and improved antiretroviral responses. As such, they may be considered for development as part of long acting antiretroviral treatment regimens.

AB - Aim: Pharmacologic agents that affect autophagy were tested for their abilities to enhance macrophage nanoformulated antiretroviral drug (ARV) depots and its slow release. Methods: These agents included URMC-099, rapamycin, metformin, desmethylclomipramine, 2-hydroxy-β-cyclodextrin (HBC) and clonidine. Each was administered with nanoformulated atazanavir (ATV) nanoparticles to human monocyte-derived macrophages. ARV retention, antiretroviral activity and nanocrystal autophagosomal formation were evaluated. Results: URMC-099, HBC and clonidine retained ATV. HBC, URMC-099 and rapamycin improved intracellular ATV retention. URMC-099 proved superior among the group in affecting antiretroviral activities. Conclusion: Autophagy inducing agents, notably URMC-099, facilitate nanoformulated ARV depots and lead to sustained release and improved antiretroviral responses. As such, they may be considered for development as part of long acting antiretroviral treatment regimens.

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KW - monocyte-derived macrophages

KW - rapamycin

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Modulating cellular autophagy for controlled antiretroviral drug release

Abstract

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