Anticancer efficacy, tissue distribution and blood pharmacokinetics of surface modified nanocarrier containing melphalan.

The objectives of the present study were to circumvent the moisture-associated instability, enhance bioavailability and achieve enhanced passive targeting of melphalan to the ovaries. Solubility of the drug was determined in various excipients to select the components of nanoemulsion. Pseudoternary phase diagrams were constructed using aqueous titration method. Formulations selected from the pseudoternary phase diagram were subjected to thermodynamic stability and dispersibility studies to select the final test formulations which were characterized for average globule size, polydispersity index (PDI), zeta potential, viscosity, refractive index, in-vitro drug release and percentage transmittance to optimize the final formulation. Pharmacokinetic and biodistribution studies of the optimized formulation in comparison to the pure drug suspension were done using γ-scintigraphy on female Balb/c mice. In-vitro cytotoxicity study on Hela cervical cancer cell lines was also done to compare the anticancer activity of the developed formulation with respect to the pure drug solution. In vitro-in vivo correlation was established for the amount of drug released and the amount of drug absorbed using suitable deconvolution. Stability studies on the final formulation were performed at 40 ± 2 °C and 75 ± 5% RH for 3 months and the shelf life was determined. Capmul MCM, Tween 80 and Transcutol P (S(mix)) were selected as the oil, surfactant and co-surfactant respectively on the basis of solubility studies. Out of 17 formulations prepared, six formulations were selected as the final test formulations on the basis of thermodynamic stress and dispersibility tests. The optimized formulation composed of oil (10%, v/v), S(mix) (35%, v/v), and double distilled water (55%, v/v). Bioavailability studies revealed 4.83 folds enhancement in bioavailability of the drug from nanoemulsion as compared to that from suspension. Biodistribution studies revealed more than 2 folds increase in uptake of the drug from nanoemulsion by ovaries as compared to that from the suspension. In vitro cytotoxicity studies demonstrated augmented anticancer potential of the drug in the form of nanoemulsion formulation in comparison to the drug solution. Level A correlation was established between the amount of drug released and the amount of drug absorbed. The shelf life of the formulation was found to be 1.30 years. The results demonstrate surface modified nanoemulsion to be a promising approach so as to increase stability, bioavailability and cellular uptake of the drug.