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Hyaluronic acid-bound letrozole nanoparticles restore sensitivity to letrozole-resistant xenograft tumors in mice.

Abstract
Letrozole is a potent aromatase inhibitor and superior to other defined selective estrogen receptor modulators such as tamoxifen in treating hormone-responsive postmenopausal breast cancer patients. Patients who receive this drug may become insensitive to the effects of estrogen deprivation induced by letrozole. Letrozole has known side effects on bone metabolism due to systemic ablation of estrogen production. The purpose of this study was to examine the therapeutic efficacy of hyaluronic acid-bound letrozole nanoparticles (HA-Letr-NPs) in restoring sensitivity to letrozole-resistant (LTLT-Ca) cells. To target letrozole to LTLT-Ca cells, hyaluronic acid-bound letrozole nanoparticles were prepared by nanoprecipitation using biodegradable PLGA-PEG co-polymer. Binding specificity of HA to CD44 on the cell surface was analyzed in vitro using FITC-CD44 Ab and CD44 siRNA by flow cytometry. Effects on in vitro cytotoxicity and aromatase enzymatic activity of HA-Letr-NPs were performed in MCF-7 breast cancer cells, MCF-7 cells over-expressing aromatase (MCF-7/Aro), and LTLT-Ca cells resistant to letrozole. Preclinical efficacy of HA-Letr-NPs was examined in mice using LTLT-Ca xenograft tumors. HA-Letr-NPs were restricted to a maximum size of 100 nm. The in vitro drug release assay showed that the highest released concentration of letrozole occurred after 23 hours at 37 degrees C in phosphate-buffered saline. HA-Letr-NPs on MCF-7/Aro and LTLT-Ca cells showed an IC50 of 2 microM and 5 microM, respectively. HA-Letr-NPs were more efficacious in inhibiting tumor growth, reducing in vitro cellular and in vivo tumor aromatase enzyme activity more than the corresponding Letr-NPs or letrozole. HA-Letr-NPs restored and maintained a prolonged sensitivity and targeted delivery of letrozole in letrozole-resistant tumors in vivo.
AuthorsHareesh B Nair, Steven Huffman, Poornachand Veerapaneni, Nameer B Kirma, Peter Binkley, Rao P Perla, Dean B Evans, Rajeshwar R Tekmal
JournalJournal of nanoscience and nanotechnology (J Nanosci Nanotechnol) Vol. 11 Issue 5 Pg. 3789-99 (May 2011) ISSN: 1533-4880 [Print] United States
PMID21780370 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Nitriles
  • Triazoles
  • letrozole
  • Hyaluronic Acid
Topics
  • Animals
  • Antineoplastic Agents (chemistry, pharmacology)
  • Apoptosis (drug effects)
  • Blotting, Western
  • Drug Resistance, Neoplasm
  • Flow Cytometry
  • Hyaluronic Acid (chemistry)
  • Mice
  • Microscopy, Electron, Scanning
  • Nanoparticles
  • Nitriles (chemistry, pharmacology)
  • RNA Interference
  • Triazoles (chemistry, pharmacology)
  • Xenograft Model Antitumor Assays

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