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Evaluation of the potential of nanostructured lipid carriers functionalized with bevacizumab for delivery of docetaxel in the treatment of glioblastoma multiforme

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Leonardo Delello Di Filippo
Total Authors: 1
Document type: Master's Dissertation
Press: Araraquara. 0000-00-00.
Institution: Universidade Estadual Paulista (Unesp). Faculdade de Ciências Farmacêuticas. Araraquara
Defense date:
Advisor: Marlus Chorilli

Glioblastoma multiforme (GBM) is the most common primary malignant cancer of the Central Nervous System, responsible for about 4% of deaths associated with neoplasms, being characterized as one of the most fatal human cancers. Chemotherapy is widely used in the treatment and, among the available drugs, docetaxel (DTX) is a chemotherapy that has been showing efficiency in the treatment of GBM, inhibiting cell proliferation from the mitotic block, preventing the depolymerization of the microtubules, making them unstable and non-functional, so the cell is unable to divide and dies from apoptosis. However, the commercial presentation of this drug, Taxotere®, has side effects associated with systemic biodistribution, as well as limited brain bioavailability, which makes its clinical use difficult. In order to overcome the blood-brain barrier (BBB) and make the drug available more efficiently, a very attractive approach is encapsulation in nanostructured lipid carriers (NLC) functionalized with specific ligands of VEGF (vascular endothelial growth factor) receptors overexpressed in GBM tumor cells, such as bevacizumab (BVZ). NLC can be useful in chemotherapy treatment, as they improve the bioavailability of drugs, being able to selectively deliver them to cancer cells, reducing systemic toxicity and increasing the effectiveness of the treatment. The current work aimed to evaluate the potential of NLC functionalized with BVZ for the delivery of docetaxel in the treatment of glioblastoma multiforme. The NLC were successfully obtained using the fusion-emulsification technique followed by ultrasonication, with sizes ranging from 110 to 149 nm, confirmed by TEM, NTA and DLS analysis, zeta potential ranging from -17.4 to -24.8 mV, as well as polydispersity index ranging from 0.148 to 0.388, in addition to presenting spherical morphology, as evidenced by transmission electron microscopy. The encapsulation efficiency (EE%) for conventional or functionalized NLC was 93.22% and 90.30% respectively. The NLC were functionalized by a BVZ thiol reaction and the functionalization efficiency (EF%) found was higher than 62%. The integrity of BVZ in the CLN after the functionalization process was confirmed by SDS-PAGE assays and fluorescence spectroscopy. DSC analyzes confirmed the thermal stability of the conventional and functionalized system. Functionalized NLC showed a gradual and sustained release profile. Cellular assays for evaluating the in vitro antitumor activity of functionalized NLC or did not demonstrate that the functionalized formulation selectively potentiated the cytotoxic activity of DTX in cells that overexpress VEGF, such as U87MG and A172, but not in healthy cells (PMBCs, basal VEGF levels), being able to reduce cell viability due to death by apoptosis. These results indicate that DTX encapsulation in BVZ functionalized NLC was able to preserve its antitumor activity and potentiate its cytotoxicity in cells that overexpress VEGF, representing an important advance in obtaining more efficient and less toxic drugs, with the help of nanotechnology. (AU)

FAPESP's process: 18/18488-3 - Potential evaluation of nanostructured lipid carriers functionalized with bevacizumab for delivery of docetaxel in the treatment of glioblastoma
Grantee:Leonardo Delello Di Filippo
Support Opportunities: Scholarships in Brazil - Master