Self-assembled micelles of monosialogangliosides as nanodelivery vehicles for taxanes.

Abstract We demonstrate herein that taxanes (paclitaxel (Ptx) and docetaxel (Dtx)) can be spontaneously loaded into ganglioside nanomicelles. The efficiency of gangliosides to solubilize taxanes was highly dependent on their self-aggregating structure. Thus, GM3 that forms unilamellar vesicles was less efficient to solubilize taxanes than gangliosides that form micelles (i.e. GM1 and GM2). Sialic acid cyclization of GM1 by acid treatment led to an important reduction in its capacity to solubilize taxanes, as also did the replacement of the fatty acid of ceramide by a dicholoracetyl group. Water solubility of paclitaxel (Ptx) is less than 1 μg mL − 1 and increased up to 6.3 mg.mL − 1 upon its association with GM1 micelles. The incorporation of Ptx in GM1 reached an optimum at GM1/Ptx 20/1 molar ratio when performed at room temperature. An increase in the solubilization capacity of GM1 micelles was observed upon dehydration of their polar head group by pre-treatment at 55 °C. Loading of Ptx into the micelle induced a structural reorganization that led to an important protection of Ptx reducing its hydrolysis at alkaline pH. Diffusion of either GM1 or Ptx was restricted upon mixed-micelle formation indicating that they are kinetically more stable than pure ganglioside micelles. X-ray powder diffraction of lyophilized GM1 micelles with Ptx showed a change in their internal structure from a crystalline state to completely amorphous. Taxane-ganglioside mixed micelles were stable in solution for at least 4 months and also upon freeze-thawing or lyophilization-solubilization cycles. Upon mixing with human blood constituents, GM1/Ptx micelles did not induce hemolysis or platelet aggregation and were spontaneously covered with human serum albumin (HSA), which could aid in the delivery of micellar content to tumors. In vitro antimitotic activity of GM1/Ptx mixed micelles was qualitatively equivalent to that of free drug in DMSO solution.