The current work was aimed to develop Medium Chain Triglyceride (MCT) rich self nanoemulsifying preconcentrate of paclitaxel (PTX) for parenteral delivery. Very high concentrations of Cremophor EL and ethanol in Taxol have rendered patients to severe side effects. Years of extensive research on development of cost effective and safer vehicle for PTX, have failed to provide a promising replacement for Taxol. MCT was selected as oil owing to its parenteral acceptability, high solubilization capacity and multiple therapeutic benefits in cancer cachexia. PTX precipitation kinetics and reported toxicity profile of Kolliphor HS15 has favored its selection for PTX Self Nanoemulsifying Preconcentrate (PSNP). Presence of 30% free PEG in Kolliphor HS15 (PEG-15-hydroxystearate) restricts its miscibility with MCT, imposing significant challenge in development of MCT rich self nanoemulsifying preconcentrate. Removal of PEG layer from oil-surfactant mixture facilitated the formulation of PSNP with 51% w/w MCT. PSNP exhibited better precipitation kinetic profile, higher PTX loading with negligible hemolysis and histamine release compared to Taxol. PSNP was bioequivalent to Taxol, though V(d) and MRT was significantly higher than Taxol. PSNP showed distinctly better profile in inhibiting tumor growth and maintaining body weight with significantly higher % survival. Thus, PSNP can be a safer vehicle with potential clinical benefits.
Surface modification of liposomes with targeting ligands is known to improve the efficacy with reduced untoward effects in treating infective diseases like visceral leishmaniasis (VL). In the present study, modified ligand (ML), designed by modifying polysaccharide with a long chain lipid was incorporated in liposomes with the objective to target amphotericin B (Amp B) to reticuloendothelial system and macrophages. Conventional liposomes (CL) and surface modified liposomes (SML) were characterized for size, shape, and entrapment efficiency (E.E.). Amp B SML with 3% w/w of ML retained the vesicular nature with particle size of ∼205 nm, E.E. of ∼95% and good stability. SML showed increased cellular uptake in RAW 264.7 cells which could be attributed to receptor-mediated endocytosis. Compared to Amp B solution, Amp B liposomes exhibited tenfold increased safety in vitro in RAW 264.7 and J774A.1 cell lines. Pharmacokinetics and biodistribution studies revealed high t , area under the curve (AUC), reduced clearance and prolonged retention in liver and spleen with Amp B SML compared to other formulations. In promastigote and amastigote models, Amp B SML showed enhanced performance with low 50% inhibitory concentration (IC) compared to Amp B solution and Amp B CL. Thus, due to the targeting ability of ML, SML has the potential to achieve enhanced efficacy in treating VL.
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