Augmented anticancer activity of naringenin-loaded TPGS polymeric nanosuspension for drug resistive MCF-7 human breast cancer cells

Abstract

Naringenin (NAR) is a naturally occurring plant flavonoid, found predominantly in citrus fruits, possesses a wide range of pharmacological properties. However, despite the therapeutic potential of NAR, its clinical development has been hindered due to low aqueous solubility and inefficient transport across biological membranes resulting in low bioavailability at tumor sites. In our previous studies, nanosuspension of naringenin (NARNS) was prepared using high pressure homogenization method using different polymers. D-α-Tocopheryl polyethylene glycol succinate 1000 (TPGS) was added as a co-stabilizer. All formulation characterization studies were performed. As a continuation of our previous research, current study has further evaluated the ability of the TPGS-coated NARNS, to reverse drug-resistance of P-gp-over expressing MCF-7 human breast adenocarcinoma cell line and animal model. MTT-based colorimetric assay revealed higher cytotoxic efficacy of NARNS than free NAR in MCF-7 cells. NARNS treatment significantly increased intracellular ROS level, mitochondrial membrane potential, caspase-3 activity, lipid peroxidation status (TBARS) and decreased GSH levels when compared to free NAR treatment in MCF-7 cells. It has been also noticed that the presence of apoptotic indices (membrane blebbing, nuclear fragmentation) in NARNS treated cancer cells. Further, NARNS exhibited dose-dependent in vitro antitumor activity with DLA cells. A significant increase in the life span and a decrease in the cancer cell number and tumor weight were noted in the tumor-induced mice after treatment with NARNS.

Development of Polymer and Surfactant Based Naringenin Nanosuspension for Improvement of Stability, Antioxidant, and Antitumour Activity

“…is nanosuspension can enter cells via endocytosis or phagocytosis resulting in higher accumulation within the cells. ese factors lead to higher efficacy of NAR nanosuspension [29,30]. Similar enhancement of cytotoxicity by the formulation of nanosuspension has been reported for naringenin and other drugs [29,30].…”

“…e in vitro study was carried out by transferring the prepared drug solution and nanosuspension into dialysis tubing, which was then immersed in phosphate buffer solution (PBS) (100 mL, pH 6.8) under magnetic stirring at 37°C at 100 rpm. 2 mL samples were withdrawn at different time intervals (5,15,30,60, and 120 min) and replaced with the same volume of fresh PBS. e samples were filtered and analyzed using a UV spectrophotometer in triplicate.…”

Stable Isotope Tracing Metabolomics to Investigate the Metabolic Activity of Bioactive Compounds for Cancer Prevention and Treatment

“…Glucose transporter (GLUT), 2. hexokinase, 3. glucose-6-phosphate dehydrogenase, 4. phosphofructokinase, 5. gyceraldehyde-3-phosphate dehydrogenase, 6. pyruvate kinase M2, 7. lactate dehydrogenase, 8. monocarboxylate transporter, 9. glutamine transporter, 10. glutamate dehydrogenase, 11. fatty acid synthase. Naringenin (a flavonoid) Citrus fruits, tomatoes, figs Inhibit insulin stimulated glucose uptake Breast, prostate, melanoma, liver [9][10][11][12][13][14][15][16][17][18][19] Inhibit ASCT2-glutamine transporter Prostate, breast, cervix [8,[84][85][86] Gracillin Inhibit mitochondrial complex II Lung, colorectum, prostate, pharynx, liver [87]…”

Direct Quantification of Drug Loading Content in Polymeric Nanoparticles by Infrared Spectroscopy

“…As a model drug, we used SFN loaded with naringenin (NAR), a natural flavonoid [ 38 , 39 ], which has recently demonstrated its good compatibility with silk fibroin [ 16 ]. NAR has received increasing attention in medicine due to its free-radical scavenging [ 40 ], anti-inflammatory [ 41 ] and anticancer properties [ 42 , 43 , 44 , 45 , 46 ]. However, NAR quantification remains a problem, especially when loaded into protein-based nanoparticles, as its absorption maximum at 289 nm overlaps the absorption of aromatic amino acids of proteins.…”