title: 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.
authors.affiliation: Department of Obstetrics and Gynecology and Cancer Therapy and Research Center, University of Texas Health Science Center at San Antonio, TX 78229, USA.
authors.forename: Hareesh B
authors.initials: HB
authors.lastname: Nair
authors.forename: Steven
authors.initials: S
authors.lastname: Huffman
authors.forename: Poornachand
authors.initials: P
authors.lastname: Veerapaneni
authors.forename: Nameer B
authors.initials: NB
authors.lastname: Kirma
authors.forename: Peter
authors.initials: P
authors.lastname: Binkley
authors.forename: Rao P
authors.initials: RP
authors.lastname: Perla
authors.forename: Dean B
authors.initials: DB
authors.lastname: Evans
authors.forename: Rajeshwar R
authors.initials: RR
authors.lastname: Tekmal
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006820:Hyaluronic Acid / Q000737:chemistry*; D000077289:Letrozole; D051379:Mice; D008855:Microscopy, Electron, Scanning; D053758:Nanoparticles; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D034622:RNA Interference; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009570:Nitriles; D014230:Triazoles; D000077289:Letrozole; D006820:Hyaluronic Acid