Potential evaluation of nanostructured lipid carriers functionalized with bevacizumab for delivery of docetaxel in the treatment of glioblastoma

Abstract

Glioblastoma (GBM) is the most common primary malignant cancer of the central nervous system, responsible for about 4% of the deaths associated with tumors, characterizing itself as one of the most fatal cancers. Chemotherapy is widely used in treatment and docetaxel (DTX), Taxotere®, is a chemotherapeutic drug that has demonstrated efficacy in GBM treatment, inhibiting cell proliferation by mitotic block, by preventing the depolymerization of microtubules , making them unstable and nonfunctional, so that the cell is not able to divide and dies by apoptosis. However, Taxotere® has side effects associated with toxicity as well as limited bioavailability, which limits its clinical use. A very attractive approach is the encapsulation in nanostructured lipid carriers (CLN), functionalized with specific ligands of receptors present on the surfaces of tumor cells, in order to overcome the blood-brain barrier (BBB) and to make the drug available more efficiently. CLNs are useful in chemotherapy because they improve the bioavailability of the drugs, being able to selectively deliver them to the cancer cells, reducing the systemic toxicity and increasing the effectiveness of the treatment. The current work aims at evaluating the potential of nanostructured lipid carriers functionalized with bevacizumab for the delivery of docetaxel in the treatment of glioblastoma. The CLNs will be obtained by the fusion-emulsification technique. The CLNs will be functionalized by the thiolation reaction of bevacizumab. The CLN will be characterized by physico-chemical techniques regarding its size, morphology, polydispersity index, zeta potential, encapsulation efficiency and functionalization efficiency. The integrity of bevacizumab in the functionalized CLNs will be verified by SDS-PAGE assays and circular dichroism. Release assays will be performed for conventional CLNs and functionalized with bevacizumab. Finally, in vitro biological assays will be performed to evaluate the cytotoxicity of the formulation in lineages that overexpress or not VEGF. Therefore, it is expected to obtain an innovative, target-specific CLN that allows targeted delivery of docetaxel in sufficient amounts as an alternative to the pharmacological treatment of GBM. (AU)