Development of graphene oxide hybrids as platform for the treatment of non-invasive bladder cancer: interactions of Bacillus Calmette-Gueri immunotherapy, metformin and RNA interference

• Grant number: 14/11154-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2015
• End date: January 31, 2017
• Field of knowledge: Health Sciences - Pharmacy - Pharmaceutical Technology
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Wagner José Fávaro
• Grantee: Joel Gonçalves de Souza
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The most widely used therapy modality for the treatment of bladder cancer (BC) is based on the intravesical administration of Bacillus Calmette-Gueri (BCG) associated with transurethral resection. The anti-tumor effects of BCG start by triggering a systemic immune response involving both humoral and cellular components through the activation of Toll-like receptors (TLR) agonists, providing anti-tumor and anti-angiogenic activity. Despite the anti-cancer activity of BCG, a significant number of patients undergoing this treatment have shown intolerance, besides potentially fatal complications, such as systemic BCG infection. Furthermore, 50 % of non-muscle invasive BC (BCNMI) tumors have recurrence within 4 years after treatment and 11 % of the cases present invasive phenotype. Metformin is a drug used in the treatment of type II diabetes. Several studies demonstrate that metformin has anti cancer activity involving different mechanisms, among them aspects concerning the cellular metabolism. Besides metformin, after the recent discovery of interference RNA (siRNA), these substances started to be studied by silencing genes associated with cancer. In this project, we aim to develop graphene oxide (GO) hybrids for simultaneous administration of metformin and siRNA for VEGF (vascular endothelial growth factor). Furthermore, we propose the association between GO hybrids containing metformin and siRNA and the conventional therapy with BCG. It is expected that such associations potentiate the anti-cancer activity compared to the administration of metformin and siRNA alone and in relation to the usual therapy with BCG. For that, the GO will be chemically modified for entrapment of those molecules. The hybrids will be characterized by physical and chemical methods such as atomic force microscopy (AFM), infrared absorption spectroscopy (FTIR), determination of zeta potential and particle size. The complexation of siRNA by GO will be evaluated by electrophoresis. The in vitro cell transfection will also be evaluated and the VEGF expression will be quantified by ELISA. Ultimately, the hybrids which provide better physicochemical properties, lower cytotoxicity and higher silencing activity under VEGF production will be investigated in vivo to determine the antitumor activity against BCNMI. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DURAN, NELSON; FAVARO, WAGNER J.; SCABRA, AMCDCA B.. What do we Really Know about Nanotoxicology of Silver Nanoparticles In vivo? New Aspects, Possible Mechanisms, and Perspectives. CURRENT NANOSCIENCE, v. 16, n. 3, p. 292-320, 2020. (14/11154-1, 18/08194-2)

DURAN, NELSON; FAVARO, WAGNER J.; SEABRA, AMEDEA B.. What do we Really Know about Nanotoxicology of Silver Nanoparticles In vivo? New Aspects, Possible Mechanisms, and Perspectives. CURRENT NANOSCIENCE, v. 17, n. 3, p. 292+, 2021. (18/08194-2, 14/11154-1)

FAVARO, WAGNER J.; DE SOUZA, JOEL G.; MATSUMOTO, MIRIAN Y.; DURAN, MARCELA; BOCKELMANN, PETRA K.; DIAS, QUEILA C.; DURAN, NELSON. Associating Graphene Oxide Derivatives to Treat Non-Muscle Invasive Bladder Cancer (NMIBC). BIOINTERFACE RESEARCH IN APPLIED CHEMISTRY, v. 12, n. 1, p. 15-pg., 2022-02-15. (14/11154-1)

FAVARO, WAGNER J.; DE SOUZA, JOEL G.; FERREIRA, LUIZ A. B.; DE JESUS, MARCELO B.; DURAN, MARCELA; BOCKELMANN, PETRA K.; BERNARDES, JULIANA S.; DURAN, NELSON. Hybrid graphene oxide as carrier of doxorubicin: cytotoxicity and preliminary in vivo assays against bladder cancer. ADVANCES IN NATURAL SCIENCES-NANOSCIENCE AND NANOTECHNOLOGY, v. 11, n. 2, JUN 2020. (14/11154-1)