Efavirenz is a non-nucleoside reverse transcriptase inhibitor, and is classified as BCS Class II API. Its erratic oral absorption and poor bioavailability make it a potential candidate for being formulated as a nanosuspension. The objective of this study was to formulate efavirenz nanosuspensions employing the antisolvent precipitation-ultrasonication method, and to enhance its solubility by reducing particle size to the nanometer range. The effects of different process parameters were studied and optimized with respect to particle size and poly dispersity index (PDI). The optimized formulation was also subjected to lyophilization, to further increase the solubility and stability, and the technology is potentially suited to a range of poorly water-soluble compounds.
Hypoxia is characterized by an inadequate supply of oxygen to tissues, and hypoxic regions are commonly found in solid tumors. The cellular response to hypoxic conditions is mediated through the activation of hypoxia-inducible factors (HIFs) that control the expression of a large number of target genes. Recent studies have shown that the receptor for advanced glycation end products (RAGE) participates in hypoxia-dependent cellular adaptation. We review recent evidence on the role of RAGE signaling in tumor biology under hypoxic conditions.
Pancreatic cancer (PC) is one of the deadliest cancers owing to its late diagnosis and chemoresistance. PC tumors are characterized by large hypoxic regions that contribute to cell proliferation and migration, tumor growth, formation of metastases and resistance to chemotherapeutic agents. Studies have shown that the Receptor for Advanced Glycation End products (RAGE) is upregulated in hypoxic conditions. In addition, RAGE has been shown to activate NF‐κB, resulting in the transcription of genes involved in cancer cell migration. The goal of our study was to determine if, under hypoxic conditions, RAGE promotes migration of pancreatic cancer cells via NF‐κB.
We performed our study in hypoxic like conditions using cobalt chloride as HIF‐1α stabilizer. The generation of hypoxic‐like conditions was determined by comparing the levels of HIF‐1α in the absence and presence of cobalt chloride, by Western blot analysis and immunofluorescence. The levels of RAGE and the p65 subunit of NF‐κB was determined by Western blot analysis as well. Cell migration was assessed using Boyden chamber assays.
As anticipated, higher levels of HIF‐1α were observed in hypoxic‐like conditions than in normoxia.RAGE and p65 expression levels were also found to be higher in hypoxic‐like conditions than in normoxia.At the cellular level, we found that a larger number of cells had migrated through the filter in the presence than in the absence of cobalt chloride. We are currently investigating how blocking RAGE activity affects the migration of pancreatic cancer cells in hypoxic‐like conditions.
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