sirolimus and coumarin

To date cancer is considered as one of the most devastating diseases due to its high rate of mortality. Preclinical studies have demonstrated that the Akt/mTOR (mammalian target of rapamycin) pathway is activated in cancers and inhibition of this pathway has great potential in anti-cancer therapy. Rapamycin, one of the most potent anti-cancer drugs, blocks Akt/mTOR function and has anti-proliferative activity in several cancers. To circumvent problems associated with rapamycin due to its poor water solubility, poor oral bioavailability, low accessibility to cancer tissues and systemic toxicity, rapamycin-loaded cubic nanoparticles (NP) were formulated with vitamin E d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) as an emulsifier for oral delivery. Cubic NP were characterised and these particles demonstrated better cytotoxicity and apoptosis compared with native rapamycin under in vitro conditions due to their enhanced cellular uptake. The molecular impact of particulate systems on the Akt/mTOR pathway were elucidated by immunoblotting. Down-regulation of different anti-apoptotic genes of this pathway indicates activation of apoptotic signals leading to MIA PaCa cell death. An in vivo study demonstrated enhanced bioavailability of rapamycin in cubic NP in comparison with native rapamycin in a mouse model with no toxicity and good biocompatibility of void cubic NP at a higher dose of oral administration. Thus, rapamycin-loaded cubic NP can be used as an effective drug delivery system to produce better rapamycin therapeutics for the treatment of cancers.

Topics: Animals; Apoptosis; Biocompatible Materials; Blotting, Western; Cell Line, Tumor; Chemical Phenomena; Coloring Agents; Coumarins; Flow Cytometry; Humans; Inhibitory Concentration 50; Membrane Potential, Mitochondrial; Mice; Microscopy, Confocal; Mitogens; Nanoparticles; Neoplasms; Particle Size; Proto-Oncogene Proteins c-akt; Sirolimus; Spectroscopy, Fourier Transform Infrared; Subcellular Fractions; Time Factors; TOR Serine-Threonine Kinases