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Docetaxel-loaded liposomes targeted with cetuximab in combination with plasmonic therapy with gold nanorods for prostate cancer treatment

Grant number: 16/02723-8
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2016
Effective date (End): January 08, 2018
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Marlus Chorilli
Grantee:Josimar de Oliveira Eloy
Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Prostate cancer represents a severe health problem issue, causing thousands of deaths annualy. The treatment of the chemotherapeutic drug docetaxel, despite presenting clinical efficacy, is associated with the development of resistance in advanced stages of the disease, also the drug presents both poor water solubility and pharmacokinetics. Therefore, it becomes relevant the employment of nanostructured delivery systems, particularly liposomes, to improve docetaxel unfavorable characteristics. Furthermore, cetuximab, a monoclonal antibody that binds to EGFR Enhanced Growth Factor receptor), overexpressed in several types of prostate tumor, represents a potential strategy for prostate cancer treatment in combination with docetaxel. Within this context, the functionalization of liposomes with ligands, such as cetuximab, for overexpressed receptors on the cell surface, generating immunoliposomes, might allow for the selective drug delivery, resulting in reduced side effects. The employment of tumor hyperthermia with plasmonic therapy mediated with PEGylated gold nanorods, represents a strategy to increase the accumulation of nanoparticles at the tumor site, with potential application to improve the efficacy of immunoliposomes. Thus, the present study will consist on the preparation, characterization and in vitro/in vivo evaluation of immunoliposomes targeted with cetuximab, loaded with docetaxel, associated or not with plasmonic therapy with gold nanorods. PEGylated nanorods, liposomes and immunoliposomes will be prepared following standard protocols. The physicochemical characterization will involve the determination of docetaxel encapsulation efficiency, antibody functionalization efficiency and integrity, determination of particle size, polydispersity, zeta potential, as well as the characterization of gold nanorods by transmission electron microscopy and near infrared-UV-visible light absorption profile. The evaluation of the cell uptake of the formulations will be investigated with confocal microscopy and flow cytometry, employing cells with higher and lower EGFR expression, with the influence or not of heat shock. Afterwards, the in vitro efficacy of the formulations will be evaluated through the MTT assay, with influence of heat shock or not. Finally, the in vivo efficacy will be conducted in prostate xenograft model, with the application or not of plasmonic therapy induced with irradiated PEGylated gold nanorods.

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