Formulations of biodegradable Nanogel carriers with 5′-triphosphates of nucleoside analogs that display a reduced cytotoxicity and enhanced drug activity

Ekta Kohli, Huai Yun Han, Arin D. Zeman, Serguei V. Vinogradov

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Therapies including nucleoside analogs are associated with severe toxic side effects and acquirement of drug resistance. We have previously reported the drug delivery in the form of 5′-triphosphates (NTP) encapsulated in cross-linked cationic networks of polyethylenimine (PEI) and PEG/Pluronic® polymers (Nanogels). In this study, Nanogels, containing biodegradable PEI that could easily dissociate in reducing cytosolic environment and form products with minimal toxicity, were synthesized and displayed low cytotoxicity. Toxicity of Nanogels was clearly dependent on the total positive charge of carriers and was 5-6 fold lower for carriers loaded with NTP. Though intracellular ATP level was immediately reduced by ca. 50% following the treatment with Nanogels, it was largely restored 24 h later. Effect of Nanogels on various respiratory components of cells was reversible too, and, therefore, resulted in low immediate cell death. Nanogel alone and formulations with AZT-TP demonstrated a much lower mitochondrial toxicity than AZT. As an example of potential antiviral applications of low-toxic Nanogel carriers, a 5′-triphosphorylated Ribavirin-Nanogel formulation was prepared that demonstrated a 30-fold decrease in effective drug concentration (EC90) and, totally, a 10-fold increase in selectivity index compared to the drug alone in MDCK cells infected with influenza A virus.

Original languageEnglish (US)
Pages (from-to)19-27
Number of pages9
JournalJournal of Controlled Release
Volume121
Issue number1-2
DOIs
StatePublished - Aug 16 2007

Fingerprint

Nucleosides
Pharmaceutical Preparations
Polyethyleneimine
Poisons
Poloxamer
Madin Darby Canine Kidney Cells
triphosphoric acid
NanoGel
Ribavirin
Influenza A virus
Cellular Structures
Drug-Related Side Effects and Adverse Reactions
Drug Resistance
Antiviral Agents
Polymers
Cell Death
Adenosine Triphosphate

Keywords

  • Delivery vehicle
  • Influenza A virus
  • Mitochondrial toxicity
  • Nanogel polymer network
  • Nucleoside analogs 5′-triphosphates

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Formulations of biodegradable Nanogel carriers with 5′-triphosphates of nucleoside analogs that display a reduced cytotoxicity and enhanced drug activity. / Kohli, Ekta; Han, Huai Yun; Zeman, Arin D.; Vinogradov, Serguei V.

In: Journal of Controlled Release, Vol. 121, No. 1-2, 16.08.2007, p. 19-27.

Research output: Contribution to journalArticle

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