Synthesis, drug release and anti-HIV activity of a series of PEGylated zidovudine conjugates

Int J Biol Macromol. 2012 May 1;50(4):974-80. doi: 10.1016/j.ijbiomac.2012.02.019. Epub 2012 Feb 25.

Abstract

A series of methoxy poly(ethylene glycol)-succinyl-5'-O-zidovudine conjugates (mPEG-succinyl-AZT) with different molecular weight (M(w): 750 Da, 2, 5 or 10 kDa) of mPEG were synthesized and characterized by Fourier transform infrared (FTIR) spectroscopy, (1)H nuclear magnetic resonance ((1)H NMR) spectroscopy, and matrix-assisted laser desorption/ionization time of flight mass (MALDI TOF MS) spectrometry analysis. All conjugates showed good stability in vitro release experiments, and good anti-HIV activity and low cytotoxicity in MT-4 cells, in which, mPEG(750)-succinyl-AZT exhibited good inhibition to wild-type viruses (strains IIIB and ROD) with EC(50) values of 0.11 and 0.090 μmol/L, respectively, and it showed no cytotoxicity up to 110 μmol/L. Oral pharmacokinetic study in rats showed the half-life time (T(1/2)) of all conjugates are prolonged compared to free AZT. Especially, mPEG(750)-succinyl-AZT displayed a ~2.3-fold prolonged half-life and approximately 224% increased bioavailability of AZT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / pharmacology*
  • Anti-HIV Agents / toxicity
  • Chemistry Techniques, Synthetic*
  • Male
  • Polyethylene Glycols / chemistry*
  • Rats
  • Rats, Wistar
  • Spectrum Analysis
  • Zidovudine / chemistry*
  • Zidovudine / pharmacokinetics
  • Zidovudine / pharmacology*
  • Zidovudine / toxicity

Substances

  • Anti-HIV Agents
  • Polyethylene Glycols
  • Zidovudine