Cancer treatment with simvastatin and drug delivered chemotherapy with paclitaxel associated to a lipid nanoemulsion

I.F. Kretzer, D.A. Maria, R.A. Fock and R.C. Maranhão
University of São Paulo, BR

Keywords: lipidic nanoemulsion, drug targeting, paclitaxel, simvastatin, cancer treatment

Summary:

A lipid nanoemulsion (LDE) was previously proposed to direct chemotherapeutic agents to neoplastic cells. Here we tested the application of this drug delivery system in combined treatment with paclitaxel and simvastatin. Melanoma bearing mice were treated with paclitaxel oleate associated to LDE with (LDE-PTX+SIMVA) or without simvastatin (LDE-PTX); commercial formulation of paclitaxel plus simvastatin (PTX+SIMVA); Simvastatin (SIMVA); and saline. Evaluation of possible toxic effects was accessed in mice without tumor. LDE-PTX+SIMVA showed negligible toxicity as compared with PTX+SIMVA which resulted in animal weight loss and myelosuppression. Treatment with LDE-PTX+SIMVA resulted in a remarkable tumor growth inhibition rate of 95%, compared to 44% for PTX+SIMVA. Moreover, LDE-PTX+SIMVA treatment resulted in metastasis development reduction and increased survival rate. In comparison to Control, tumors from LDE-PTX+SIMVA group presented increased expression of p21 and decreased expression of cyclin D1. Histology revealed that LDE-PTX+SIMVA presented tumors with reduced cell density and increased presence of collagen fibers. All treatments led to a reduction in the immunohistochemical expression of ICAM, MCP-1 and MMP-9 and tumors from LDE-PTX+SIMVA group presented the lowest percentage of area stained for MMP-9. Combined therapy with LDE-PTX+SIMVA was less toxic and more effective in promoting tumor growth inhibiton than the therapy with PTX+SIMVA.