A long acting nanoformulated lamivudine ProTide

Nathan Smith; Aditya N. Bade; Dhruvkumar Soni; Nagsen Gautam; Yazen Alnouti; Jonathan Herskovitz; Ibrahim M. Ibrahim; Melinda S. Wojtkiewicz; Bhagya Laxmi Dyavar Shetty; Jo Ellyn McMillan; Howard E. Gendelman; Benson Edagwa

doi:10.1016/j.biomaterials.2019.119476

A long acting nanoformulated lamivudine ProTide

Nathan Smith, Aditya N. Bade, Dhruvkumar Soni, Nagsen Gautam, Yazen Alnouti, Jonathan Herskovitz, Ibrahim M. Ibrahim, Melinda S. Wojtkiewicz, Bhagya Laxmi Dyavar Shetty, Jo Ellyn McMillan, Howard E. Gendelman, Benson Edagwa

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

27 Scopus citations

Abstract

A long acting (LA) hydrophobic and lipophilic lamivudine (3TC) was created as a phosphoramidate pronucleotide (designated M23TC). M23TC improved intracellular delivery of active triphosphate metabolites and enhanced antiretroviral and pharmacokinetic (PK) profiles over the native drug. A single treatment of human monocyte derived macrophages (MDM) with nanoformulated M23TC (NM23TC) improved drug uptake, retention, intracellular 3TC triphosphates and antiretroviral activities in MDM and CD4⁺ T cells. PK tests of NM23TC administered to Sprague Dawley rats demonstrated sustained prodrug and drug triphosphate levels in blood and tissues for 30 days. The development of NM23TC remains a substantive step forward in producing LA slow effective release antiretrovirals for future clinical translation.

Original language	English (US)
Article number	119476
Journal	Biomaterials
Volume	223
DOIs	https://doi.org/10.1016/j.biomaterials.2019.119476
State	Published - Dec 2019

Keywords

Antiretroviral therapy
Formulation
Lamivudine
Long-acting
ProTide
Prodrug

ASJC Scopus subject areas

Bioengineering
Ceramics and Composites
Biophysics
Biomaterials
Mechanics of Materials

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10.1016/j.biomaterials.2019.119476

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title = "A long acting nanoformulated lamivudine ProTide",

abstract = "A long acting (LA) hydrophobic and lipophilic lamivudine (3TC) was created as a phosphoramidate pronucleotide (designated M23TC). M23TC improved intracellular delivery of active triphosphate metabolites and enhanced antiretroviral and pharmacokinetic (PK) profiles over the native drug. A single treatment of human monocyte derived macrophages (MDM) with nanoformulated M23TC (NM23TC) improved drug uptake, retention, intracellular 3TC triphosphates and antiretroviral activities in MDM and CD4+ T cells. PK tests of NM23TC administered to Sprague Dawley rats demonstrated sustained prodrug and drug triphosphate levels in blood and tissues for 30 days. The development of NM23TC remains a substantive step forward in producing LA slow effective release antiretrovirals for future clinical translation.",

keywords = "Antiretroviral therapy, Formulation, Lamivudine, Long-acting, ProTide, Prodrug",

author = "Nathan Smith and Bade, {Aditya N.} and Dhruvkumar Soni and Nagsen Gautam and Yazen Alnouti and Jonathan Herskovitz and Ibrahim, {Ibrahim M.} and Wojtkiewicz, {Melinda S.} and {Dyavar Shetty}, {Bhagya Laxmi} and McMillan, {Jo Ellyn} and Gendelman, {Howard E.} and Benson Edagwa",

note = "Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",

year = "2019",

month = dec,

doi = "10.1016/j.biomaterials.2019.119476",

language = "English (US)",

volume = "223",

journal = "Biomaterials",

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AU - Smith, Nathan

AU - Bade, Aditya N.

AU - Soni, Dhruvkumar

AU - Gautam, Nagsen

AU - Alnouti, Yazen

AU - Herskovitz, Jonathan

AU - Ibrahim, Ibrahim M.

AU - Wojtkiewicz, Melinda S.

AU - Dyavar Shetty, Bhagya Laxmi

AU - McMillan, Jo Ellyn

AU - Gendelman, Howard E.

AU - Edagwa, Benson

PY - 2019/12

Y1 - 2019/12

N2 - A long acting (LA) hydrophobic and lipophilic lamivudine (3TC) was created as a phosphoramidate pronucleotide (designated M23TC). M23TC improved intracellular delivery of active triphosphate metabolites and enhanced antiretroviral and pharmacokinetic (PK) profiles over the native drug. A single treatment of human monocyte derived macrophages (MDM) with nanoformulated M23TC (NM23TC) improved drug uptake, retention, intracellular 3TC triphosphates and antiretroviral activities in MDM and CD4+ T cells. PK tests of NM23TC administered to Sprague Dawley rats demonstrated sustained prodrug and drug triphosphate levels in blood and tissues for 30 days. The development of NM23TC remains a substantive step forward in producing LA slow effective release antiretrovirals for future clinical translation.

AB - A long acting (LA) hydrophobic and lipophilic lamivudine (3TC) was created as a phosphoramidate pronucleotide (designated M23TC). M23TC improved intracellular delivery of active triphosphate metabolites and enhanced antiretroviral and pharmacokinetic (PK) profiles over the native drug. A single treatment of human monocyte derived macrophages (MDM) with nanoformulated M23TC (NM23TC) improved drug uptake, retention, intracellular 3TC triphosphates and antiretroviral activities in MDM and CD4+ T cells. PK tests of NM23TC administered to Sprague Dawley rats demonstrated sustained prodrug and drug triphosphate levels in blood and tissues for 30 days. The development of NM23TC remains a substantive step forward in producing LA slow effective release antiretrovirals for future clinical translation.

KW - Antiretroviral therapy

KW - Formulation

KW - Lamivudine

KW - Long-acting

KW - ProTide

KW - Prodrug

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JO - Biomaterials

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ER -

A long acting nanoformulated lamivudine ProTide

Abstract

Keywords

ASJC Scopus subject areas

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