Hyaluronic Acid Nanohydrogel Loaded With Quercetin Alone or in Combination to a Macrolide Derivative of Rapamycin RAD001 (Everolimus) as a New Treatment for Hormone‐Responsive Human Breast Cancer

Abstract

The aim of this study is based on the evaluation of anticancer, anti-inflammatory activities, and cellular uptake of hyaluronic acid nanohydrogel of quercetin tested alone and in combination to a macrolide derivative of rapamycin RAD001 (everolimus) on hormone-responsive breast cancer cell line MCF-7. Biological investigations were focused on the receptor mediated cellular internalization of the nanohydrogel and its abilities to reduce secretion of several cytokines (IL-8, IL-6, IL-19), VEGF, and metalloproteases (MMP-2, MMP-9) under pro-inflammatory conditions. Nanohydrogel show a CD44 dependent endocytosis with evident time dependent cytoplasmatic accumulation with abilities to reduce secretion of all cytokines of ∼60% compared to untreated cells. Combination of formulated quercetin and everolimus leads to a synergistic cytotoxic effects with a Combination Index of 0.38. These results highlights the importance of synergistic effect of the hyaluronic acid nanohydrogel of quercetin with everolimus in the regulation of human breast cancer cell proliferation and emphasize the antitumor and anti-inflammatory properties of the nanocarrier. J. Cell. Physiol. 232: 2063-2074, 2017. © 2016 Wiley Periodicals, Inc.

Novel nanohydrogel of hyaluronic acid loaded with quercetin alone and in combination with temozolomide as new therapeutic tool, CD44 targeted based, of glioblastoma multiforme

“…As previously demonstrated by our research group (Quagliariello, Armenia, et al, ) the uptake of fluorescent hyaluronic acid nanohydrogel (FA‐HA hydro) has a time dependent accumulation in cancer cells with a characteristic behavior of a receptor mediated targeting (an hyperbolic trend). Interestingly, just after 2h of incubation, 30% of the nanohydrogel is internalized or otherwise adhering to cell membrane of GBM cells with the same trend for both cell lines.…”

“…Hyaluronic acid nanohydrogel was prepared by solvent–non solvent method, as described by our research group (Quagliariello, Armenia, et al, ). Briefly, a 0.5% w/v HA sodium salt solution in bidistilled water was added dropwise (1 ml/min) to an equal volume of DMSO (1:1v/v ratio) under magnetic stirring (75 × g).…”

“…Quercetin has antihistamine, antiviral, immunomodulatory, and antioxidant properties and recently it has shown antitumor activity, which can induce apoptosis of different tumor cells including leukemic cells, medullary and papillary thyroid cancer, pancreatic tumor, breast cancer, hepatocarcinoma, prostate cancer, and glioblastoma (Pan et al, ; Vidak, Rozman, & Komel, ). Its mechanism of action is principally based on the cell cycle regulation, tyrosine kinase inhibition (Quagliariello, Armenia, et al, ) inhibition of cytokine and interleukin secretion (Quagliariello, Iaffaioli, et al, ), AMPK‐Sclerosis Tuberous Complex (TSC) activation and AKT‐mTOR axis inhibition (Lu et al, ) but the main clinical limitation is based on its low bioavailability due to oxidation in biological environment with a not efficient accumulation in cancer cell cytoplasm (Nam et al, ). On the basis of these limitations it would be useful to develop nanocarriers to enhance quercetin delivery protecting it from the oxidative and enzymatic environment and simultaneously achieving a more specific and controlled release in glioblastoma cells.…”

Quercetin‐mediated regulation of signal transduction cascades and microRNAs: Natural weapon against cancer

“…14 Retinoblastoma (RB), a malignant intraocular cancer was found to be difficult to target. 16 Furthermore, killing effects were further enhanced when combined with macrolide derivatives of rapamycin RAD001 (everolimus). Quercetin also dosedependently reduced mRNA of VEGFR.…”

“…15 Quercetin reduced the amount and distribution of VEGFR in Y79 cells. 16 Gold nanoparticles-conjugated quercetin suppressed migratory and invasive potential of MCF-7 and MDA-MB-231 cells. 15 Hyaluronic acid nanohydrogels loaded with quercetin were noted to be very effective against breast cancer cells.…”