Polymeric micelles loaded with glyburide and vanillic acid: I. Formulation development, in-vitro characterization and bioavailability studies.

The co-formulation of glyburide (Gly) and vanillic acid (VA) as such in the form of nanomedicine has never been explored to treat metabolic diseases including type 2 diabetes mellitus. Both the drugs possess dissolution rate-limited oral bioavailability leading to poor therapeutic efficacy. Hence, co-loading these drugs into a nanocarrier could overcome their poor oral bioavailability related challenges. Owing to this objective, both drugs were co-loaded in amphiphilic polymeric micelles (APMs) and evaluated for their biopharmaceutical outcomes. The APMs were prepared using mPEG-b-PCL/CTAB as a copolymer-surfactant system via the liquid antisolvent precipitation (LAP) method. The design of these APMs were optimized using Box Behnken Design by taking various process/formulation based variables to achieve the desired micellar traits. The release of both the drugs from the optimized co-loaded APMs was compared in different media and displayed a remarkable sustained release profile owing to their hydrophobic interactions with the PCL core. The in vitro cytotoxicity study of co-loaded APMs on Caco-2 cells revealed 70 % cell viability in a concentration-dependent manner. The preventive effects of Gly and VA co-loaded in APMs on glucose uptake was studied in insulin-responsive human HepG2 cells treated with high glucose. The co-loading of both the drugs in optimized APMs exhibited synergistic glucose-lowering activity (p < 0.001) than raw drugs with low cytotoxicity on HepG2 cells within the test concentration. This could be attributed to an increase in the relative oral bioavailability of both the drugs in APMs i.e., 868 % for Gly and 87 % for VA respectively.

Targeted Inhibition of Anti-Inflammatory Regulator Nrf2 Results in Breast Cancer Retardation In Vitro and In Vivo.

Nuclear factor erythroid-2 related factor-2 (Nrf2) is an oxidative stress-response transcriptional activator that promotes carcinogenesis through metabolic reprogramming, tumor promoting inflammation, and therapeutic resistance. However, the extension of Nrf2 expression and its involvement in regulation of breast cancer (BC) responses to chemotherapy remain largely unclear. This study determined the expression of Nrf2 in BC tissues (n = 46) and cell lines (MDA-MB-453, MCF-7, MDA-MB-231, MDA-MB-468) with diverse phenotypes. Immunohistochemical (IHC)analysis indicated lower Nrf2 expression in normal breast tissues, compared to BC samples, although the difference was not found to be significant. However, pharmacological inhibition and siRNA-induced downregulation of Nrf2 were marked by decreased activity of NADPH quinone oxidoreductase 1 (NQO1), a direct target of Nrf2. Silenced or inhibited Nrf2 signaling resulted in reduced BC proliferation and migration, cell cycle arrest, activation of apoptosis, and sensitization of BC cells to cisplatin in vitro. Ehrlich Ascites Carcinoma (EAC) cells demonstrated elevated levels of Nrf2 and were further tested in experimental mouse models in vivo. Intraperitoneal administration of pharmacological Nrf2 inhibitor brusatol slowed tumor cell growth. Brusatol increased lymphocyte trafficking towards engrafted tumor tissue in vivo, suggesting activation of anti-cancer effects in tumor microenvironment. Further large-scale BC testing is needed to confirm Nrf2 marker and therapeutic capacities for chemo sensitization in drug resistant and advanced tumors.

Design and evaluation of cabazitaxel loaded NLCs against breast cancer cell lines.

Cabazitaxel (CBZ) is a taxane derivative and an anti-microtubule agent effective against numerous cancers including drug-resistant cancers. In this study, CBZ loaded nanostructured lipid carriers (NLCs) were prepared by using Design-Expert (DoE) and optimized for various formulation parameters (ratio of lipids and surfactant concentration, homogenization speed and time). The optimized CBZ loaded NLCs formulation was characterized and evaluated through multiple physicochemical characterization techniques like FTIR, DSC, PXRD, SEM and in-vitro drug release. FTIR and DSC results suggested that NLCs entrapped drug inside and had no chemical bonding between drug and NLCs. SEM analysis confirmed homogeneous, spherical, and uniformly distributed NLCs. In-vitro cell culture studies suggested that CBZ loaded NLCs produced ∼ 6- and 2.5-times higher cytotoxicity against MDA-MB-468 and MCF-7 cell lines, respectively compared to pure drug. Cellular uptake of NLC was ∼2.5 and 2.1-fold higher than CBZ alone in MDA-MB-468 and MCF-7 cell lines, respectively. Furthermore, CBZ loaded NLCs produced significantly higher apoptosis and inhibited the mobility of MDA-MB-468 and MCF-7 cells. The results from this study demonstrate the utility of CBZ loaded NLCs as an effective treatment against breast cancer and NLCs as effective drug carriers to deliver the highly lipophilic drug such as CBZ.