Microemulsion for Prolonged Release of Fenretinide in the Mammary Tissue and Prevention of Breast Cancer Development

Abstract

The need of pharmacological strategies to preclude breast cancer development motivated us to develop a non-aqueous microemulsion (ME) capable of forming a depot after administration in the mammary tissue and uptake of interstitial fluids for prolonged release of the retinoid fenretinide. The selected ME was composed of phosphatidylcholine/tricaprylin/propylene glycol (45:5:50, w/w/w) and presented a droplet diameter of 175.3 ± 8.9 nm. Upon water uptake, the ME transformed successively into a lamellar phase, gel, and a lamellar phase-containing emulsion in vitro as the water content increased and released 30% of fenretinide in vitro after 9 days. Consistent with the slow release, the ME formed a depot in cell cultures and increased fenretinide IC50 values by 68.3- and 13.2-fold in MCF-7 and T-47D cells compared to a solution, respectively. At non-cytotoxic concentrations, the ME reduced T-47D cell migration by 75.9% and spheroid growth, resulting in ∼30% smaller structures. The depot formed in vivo prolonged a fluorochrome release for 30 days without producing any sings of local irritation. In a preclinical model of chemically induced carcinogenesis, ME administration every 3 weeks for 3 months significantly reduced (4.7-fold) the incidence of breast tumors and increased type II collagen expression, which might contribute to limit spreading. These promising results support the potential ME applicability as a preventive therapy of breast cancer.

Thermosensitive Polymeric Nanoparticles for Drug Co-Encapsulation and Breast Cancer Treatment

“…A week after the final treatment, the animals were euthanized for mammary gland dissection. The glands were divided into two sets: One set was fixed in 10% neutral buffered formaldehyde for histological analysis, involving staining (hematoxylin–eosin) and examining epithelial hyperplasia or hypertrophy, proliferation/desquamation in ducts, hyperplastic nodules, and changes in surrounding connective tissue [ 56 ]. The second set underwent homogenization for piplartine level analysis using HPLC.…”

Phosphatidylcholine-Based Nanoemulsions for Paclitaxel and a P-Glycoprotein Inhibitor Delivery and Breast Cancer Intraductal Treatment

“…To evaluate whether paclitaxel and elacridar were released from the selected NE, the formulation was placed in the receiver compartment of Franz diffusion cells in small dialysis bags (14,000 Da cutoff, Sigma-Aldrich, St. Louis, MO, USA) in phosphate buffered saline (PBS) + 1% polysorbate 80, pH 7.4, at 37 • C under stirring (150 rpm) as previously described [93]. Aliquots of the receptor phase were then withdrawn (0.25 mL) at predetermined time periods (3-24 h) and the samples were analyzed by HPLC using a Shimadzu HPLC system equipped with a Phenomenex C18 column [16,59].…”

“…Calibration curves of paclitaxel (0.2-100 µg/mL, R 2 > 0.995) or elacridar (2-20 µg/mL, R 2 > 0.993) prepared in methanol were used for drug quantification. Data were fitted to the zero-order kinetics (Q t = Q 0 + K 0 t); Higuchi kinetics (Q = K h t 1/2 ); and first-order kinetics (log Q t = −K t /2303 + log Q 0 ), in which Q t represents the absolute amount of drug released in t (time in hours), Q 0 is the initial amount of drug in the solution, K 0 is a zero-order kinetic constant, and K h is the Higuchi dissolution constant [93].…”

“…Spheroids of MCF-7 and MDA-MB-231 were obtained using the liquid overlay technique, which does not allow adhesion to the plate surface [10,93]. Accordingly, 96-well microplates were prepared with 50 µL of 1% agarose solution in each well [93], 5 × 10 3 cells/well were seeded, the plate was centrifuged at 1000 RPM for 7 min, and incubated at 37 • C in a 5% CO 2 incubator.…”

Oral sorafenib-loaded microemulsion for breast cancer: evidences from the in-vitro evaluations and pharmacokinetic studies

“…Microemulsions are not nanoemulsions, though their droplet size is in the range of 10–300 nm, the difference lies in the thermodynamic stability, methodology and composition 19 – 21 . Previously, several research groups have explored the efficacy of ME based formulations in the oral delivery of anticancer drugs 22 – 24 . Inclusion of phospholipids are known to improve the safety and efficacy of the therapeutic moiety, when incorporated in the nanocarriers by one or other means 25 .…”