Cross-linked polymeric nanogel formulations of 5′-triphosphates of nucleoside analogues: Role of the cellular membrane in drug release

Serguei V. Vinogradov, Ekta Kohli, Arin D. Zeman

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

Activation of cytotoxic nucleoside analogues in vivo depends primarily on their cell-specific phosphorylation. Anticancer chemotherapy using nucleoside analogues may be significantly enhanced by intracellular administration of active phosphorylated drugs. However, the cellular transport of anionic compounds is very ineffective and restricted by many drug efflux transporters. Recently developed cationic nanogel carriers can encapsulate large amounts of nucleoside 5′-triphosphates that form polyionic complexes with protonated amino groups on the polyethylenimine backbone of the nanogels. In this paper, the 5′-triphosphate of an antiviral nucleoside analogue, 3′-azido-2′,3′-dideoxythymidine (AZT), was efficiently synthesized and its complexes with nanogels were obtained and evaluated as potential cytotoxic drug formulations for treatment of human breast carcinoma cells. A selective phosphorylating reagent, trisimidazolylphosphate, was used to convert AZT into the nucleoside analogue 5′-triphosphate using a one-pot procedure. The corresponding 3′-azido-2′,3′-dideoxythymidine 5′-triphosphate (AZTTP) was isolated with high yield (75%). Nanogels encapsulated up to 30% of AZTTP by weight by mixing solutions of the carrier and the drug. The AZTTP/nanogel formulation showed enhanced cytotoxicity in two breast cancer cell lines, MCF-7 and MDA-MB-231, demonstrating IC50 values 130-200 times lower than those values for AZT alone. The exact mechanism of drug release from nanogels remains unclear. One mechanism could involve interaction with negatively charged counterions. A high affinity of nanogels to isolated cellular membranes has been observed, especially for nanogels made of amphiphilic block copolymer, Pluronic P85. Cellular trafficking of nanogel particles, contrasted by polyethylenimine-coordinated copper(II) ions, was studied by transmission electron microscopy (TEM), which revealed membranotropic properties of nanogels. A substantial release of encapsulated drug was observed following interactions of drug-loaded nanogels with cellular membranes. A drug release mechanism triggered by interaction of the drug-loaded nanogels with phospholipid bilayer is proposed. The results illustrate therapeutic potential of the phosphorylated nucleoside analogues formulated in nanosized cross-linked polymeric carriers for cancer chemotherapy.

Original languageEnglish (US)
Pages (from-to)449-461
Number of pages13
JournalMolecular Pharmaceutics
Volume2
Issue number6
DOIs
StatePublished - Nov 1 2005

Fingerprint

Nucleosides
Membranes
Polyethyleneimine
Drug Interactions
Drug Liberation
triphosphoric acid
NanoGel
Breast Neoplasms
Drug Therapy
Drug Compounding
Drug Carriers
Transmission Electron Microscopy
Pharmaceutical Preparations
Inhibitory Concentration 50
Antiviral Agents
Copper
Phospholipids
Phosphorylation
Ions
Weights and Measures

Keywords

  • 3′-azido-2′,3′-dideoxythymidine 5′-triphosphate
  • Cancer
  • Cellular trafficking
  • Cytotoxicity
  • Membrane
  • Nanogels
  • Synthesis

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science

Cite this

Cross-linked polymeric nanogel formulations of 5′-triphosphates of nucleoside analogues : Role of the cellular membrane in drug release. / Vinogradov, Serguei V.; Kohli, Ekta; Zeman, Arin D.

In: Molecular Pharmaceutics, Vol. 2, No. 6, 01.11.2005, p. 449-461.

Research output: Contribution to journalArticle

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abstract = "Activation of cytotoxic nucleoside analogues in vivo depends primarily on their cell-specific phosphorylation. Anticancer chemotherapy using nucleoside analogues may be significantly enhanced by intracellular administration of active phosphorylated drugs. However, the cellular transport of anionic compounds is very ineffective and restricted by many drug efflux transporters. Recently developed cationic nanogel carriers can encapsulate large amounts of nucleoside 5′-triphosphates that form polyionic complexes with protonated amino groups on the polyethylenimine backbone of the nanogels. In this paper, the 5′-triphosphate of an antiviral nucleoside analogue, 3′-azido-2′,3′-dideoxythymidine (AZT), was efficiently synthesized and its complexes with nanogels were obtained and evaluated as potential cytotoxic drug formulations for treatment of human breast carcinoma cells. A selective phosphorylating reagent, trisimidazolylphosphate, was used to convert AZT into the nucleoside analogue 5′-triphosphate using a one-pot procedure. The corresponding 3′-azido-2′,3′-dideoxythymidine 5′-triphosphate (AZTTP) was isolated with high yield (75{\%}). Nanogels encapsulated up to 30{\%} of AZTTP by weight by mixing solutions of the carrier and the drug. The AZTTP/nanogel formulation showed enhanced cytotoxicity in two breast cancer cell lines, MCF-7 and MDA-MB-231, demonstrating IC50 values 130-200 times lower than those values for AZT alone. The exact mechanism of drug release from nanogels remains unclear. One mechanism could involve interaction with negatively charged counterions. A high affinity of nanogels to isolated cellular membranes has been observed, especially for nanogels made of amphiphilic block copolymer, Pluronic P85. Cellular trafficking of nanogel particles, contrasted by polyethylenimine-coordinated copper(II) ions, was studied by transmission electron microscopy (TEM), which revealed membranotropic properties of nanogels. A substantial release of encapsulated drug was observed following interactions of drug-loaded nanogels with cellular membranes. A drug release mechanism triggered by interaction of the drug-loaded nanogels with phospholipid bilayer is proposed. The results illustrate therapeutic potential of the phosphorylated nucleoside analogues formulated in nanosized cross-linked polymeric carriers for cancer chemotherapy.",
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