Self-Assembling Raloxifene Loaded Mixed Micelles: Formulation Optimization, In Vitro Cytotoxicity and In Vivo Pharmacokinetics

Abstract

Raloxifene (RLX) has been strongly recommended for postmenopausal women at high risk of invasive breast cancer and for prevention of osteoporosis. However, low aqueous solubility and reduced bioavailability hinder its clinical application. The objective of this study was to explore the potential of RLX loaded mixed micelles (RLX-MM) using Pluronic F68 and Gelucire 44/14 for enhanced bioavailability and improved anticancer activity on human breast cancer cell line (MCF-7). RLX-MM were prepared by solvent evaporation method and optimized using 3 factorial design. The average size, entrapment efficiency and zeta potential of the optimized formulation were found to be 190 ± 3.3 nm, 79 ± 1.3%, 13 ± 0.8 mV, respectively. In vitro study demonstrated 74.68% drug release from RLX-MM in comparison to 42.49% drug release from RLX dispersion. According to the in vitro cytotoxicity assay, GI values on MCF-7 breast cancer cell line for RLX-MM and free RLX were found to be 22.5 and 94.71 μg/mL, respectively. Significant improvement (P < 0.05) in the anticancer activity on MCF-7 cell line was observed in RLX-MM over RLX pure drug. Additionally, oral bioavailability of RLX-MM was improved by 1.5-fold over free RLX when administered in female Wistar rats. Incorporation of RLX in the hydrophobic core and improved solubility of the drug due to hydrophilic shell attributed to the enhanced cytotoxicity and bioavailability of RLX-MM. This research establishes the potential of RLX loaded mixed micelles of Pluronic F68 and Gelucire 44/14 for improved bioavailability and anticancer activity on MCF-7 cell line.

RETRACTED: Lipidic Nano-Sized Emulsomes Potentiates the Cytotoxic and Apoptotic Effects of Raloxifene Hydrochloride in MCF-7 Human Breast Cancer Cells: Factorial Analysis and In Vitro Anti-Tumor Activity Assessment

“…Earlier studies reported an antiproliferative effect of RLX on MCF-7 cells for up to 100 μg/mL in concentration. For instance, pure RLX and RLX-loaded mixed micelles using Pluronic F68 and Gelucire 44/14 exhibited IC 50 values of 94.71 and 22.5 μg/mL, respectively on MCF-7 cells [ 8 ]. Additionally, Kim, D et al reported the use of about 5 μg/mL of RLX to kill 50% of MCF-7 cells within 48 h [ 52 ].…”

“…RLX has been reported to stimulate gene promoters regulated by ERβ subtype that guards against tumor formation in response to estrogen; therefore, it exhibits anti-tumor activity in breast cancer cells [ 6 ]. Nevertheless, RLX suffers from poor aqueous solubility and exposure to dramatic pre-systemic metabolism that lead to diminished bioavailability that does not surpass 2% [ 7 , 8 ].…”

Novel Intranasal Drug Delivery: Geraniol Charged Polymeric Mixed Micelles for Targeting Cerebral Insult as a Result of Ischaemia/Reperfusion

“…Such changes suggested that the functional groups of geraniol oil were included and interacted with the formulation functional groups. Thus, geraniol oil was successfully encapsulated inside the prepared mixed micelles [31,58], as shown in Figure 3. which means more abundance of O and OH points that enhance attachment to the drug molecule via hydrogen bonds leading to slower release rate [57].…”

“…Such changes suggested that the functional groups of geraniol oil were included and interacted with the formulation functional groups. Thus, geraniol oil was successfully encapsulated inside the prepared mixed micelles [31,58], as shown in Figure 3.…”

“…Briefly, a known amount of MM was dissolved in methanol to quantify the geraniol concentration. The DL and EE were calculated by the following equations: The release profile of geraniol from optimized mixed micelles formulae was studied using the dialysis method [30,31]. In brief, samples were added into previously soaked dialysis bags (HIMEDIA, molecular weight cut off 12,000-14,000 KD).…”