Stearoyl gemcitabine nanoparticles overcome resistance related to the over-expression of ribonucleotide reductase subunit M1

J Control Release. 2012 Jan 10;157(1):132-40. doi: 10.1016/j.jconrel.2011.08.004. Epub 2011 Aug 7.

Abstract

Gemcitabine is a deoxycytidine analog used in the treatment of various solid tumors. However, tumors often develop resistances over time, which becomes a major issue for most gemcitabine-related chemotherapies. In the present study, a previously reported stearoyl gemcitabine nanoparticle formulation (GemC18-NPs) was evaluated for its ability to overcome gemcitabine resistance. In the wild type CCRF-CEM human leukemia cells, the IC(50) value of GemC18-NPs was 9.5-fold greater than that of gemcitabine hydrochloride (HCl). However, in the CCRF-CEM-AraC-8C cells that are deficient in the human equilibrative nucleoside transporter-1, the IC(50) of GemC18-NPs was only 3.4-fold greater than that in the parent CCRF-CEM cells, whereas the IC(50) of gemcitabine HCl was 471-fold greater than that in the parent CCRF-CEM cells. The GemC18-NPs were also more cytotoxic than gemcitabine HCl in the deoxycytidine kinase deficient (CCRF-CEM/dCK(-/-)) tumor cells. Similar to gemcitabine HCl, GemC18-NPs induced apoptosis through caspase activation. Another gemcitabine-resistant tumor cell line, TC-1-GR, was developed in our laboratory. In the TC-1-GR cells, the IC(50) of GemC18-NPs was only 5% of that of gemcitabine HCl. Importantly, GemC18-NPs effectively controlled the growth of gemcitabine resistant TC-1-GR tumors in mice, whereas the molar equivalent dose of gemcitabine HCl did not show any activity against the growth of the TC-1-GR tumors. Proteomics analysis revealed that the TC-1-GR cells over-expressed ribonucleotide reductase M1, which was likely the cause of the acquired gemcitabine resistance in the TC-1-GR cells. To our best knowledge, this represents the first report demonstrating that a nanoparticle formulation of gemcitabine overcomes gemcitabine resistance related to ribonucleotide reductase M1 over-expression.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Chemistry, Pharmaceutical
  • Deoxycytidine / administration & dosage
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / chemistry
  • Dose-Response Relationship, Drug
  • Drug Resistance, Bacterial / drug effects*
  • Drug Resistance, Bacterial / physiology
  • Female
  • Gene Expression Regulation, Enzymologic*
  • Humans
  • Mice
  • Mice, Nude
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Random Allocation
  • Stearates / administration & dosage*
  • Stearates / chemistry
  • Tumor Suppressor Proteins / biosynthesis*

Substances

  • Stearates
  • Tumor Suppressor Proteins
  • Deoxycytidine
  • gemcitabine
  • RRM1 protein, human