Synthesis of a long acting nanoformulated emtricitabine ProTide

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

Research output: Contribution to journalArticle

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Abstract

While antiretroviral therapy (ART) has revolutionized treatment and prevention of human immunodeficiency virus type one (HIV-1) infection, regimen adherence, viral mutations, drug toxicities and access stigma and fatigue are treatment limitations. These have led to new opportunities for the development of long acting (LA) ART including implantable devices and chemical drug modifications. Herein, medicinal and formulation chemistry were used to develop LA prodrug nanoformulations of emtricitabine (FTC). A potent lipophilic FTC phosphoramidate prodrug (M2FTC) was synthesized then encapsulated into a poloxamer surfactant (NM2FTC). These modifications extended the biology, apparent drug half-life and antiretroviral activities of the formulations. NM2FTC demonstrated a >30-fold increase in macrophage and CD4+ T cell drug uptake with efficient conversion to triphosphates (FTC-TP). Intracellular FTC-TP protected macrophages against an HIV-1 challenge for 30 days. A single intramuscular injection of NM2FTC, at 45 mg/kg native drug equivalents, into Sprague Dawley rats resulted in sustained prodrug levels in blood, liver, spleen and lymph nodes and FTC-TP in lymph node and spleen cells at one month. In contrast, native FTC-TPs was present for one day. These results are an advance in the transformation of FTC into a LA agent.

Original languageEnglish (US)
Article number119441
JournalBiomaterials
Volume222
DOIs
Publication statusPublished - Nov 2019

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Keywords

  • Emtricitabine
  • Formulation
  • Long-acting slow effective release anti-retroviral therapy (LASER) ART
  • Prodrug

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Cite this

Soni, D., Bade, A. N., Gautam, N., Herskovitz, J., Ibrahim, I. M., Smith, N., ... Edagwa, B. J. (2019). Synthesis of a long acting nanoformulated emtricitabine ProTide. Biomaterials, 222, [119441]. https://doi.org/10.1016/j.biomaterials.2019.119441