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THERAPEUTIC EFFICACY OF INDOMETHACIN AND INDOMETHACIN ETHYL ESTER NANOCAPSULES IN THE CEREBRAL MICROCIRCULATION OF MICE: IN VIVO AND EX VIVO STUDIES

Grant number: 11/02438-8
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2011
Effective date (End): August 31, 2014
Field of knowledge:Biological Sciences - Pharmacology - General Pharmacology
Principal researcher:Sandra Helena Poliselli Farsky
Grantee:Stephen Fernandes de Paula Rodrigues
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

In recent years, nanotechnology has emerged as an important tool for development of new products in various areas, including pharmaceuticals. Among the various nanotechnology products available, the nanoparticle systems are highlighted by sustained drug vectoring and by acting as carriers of drugs, increasing the therapeutic efficacy. These characteristics are fundamental for the treatment of many diseases, among which the tumors. Despite the numerous advantages of anticancer nanoparticles, pharmacological and toxicological parameters of these treatment strategies must be better understood. In this context, this study aims to evaluate the anti-carcinogenic activity and the possible toxic effects of indomethacin and indomethacin ethyl ester nanocapsules (associated or not) and its usual formulation. To this end, in vivo testing will be performed in C57BL6 mice. The brain tumor will be in vivo induced by intracranial inoculation of the mouse malignant glioma cell line GL261, 10 days before treatments beginning. The treatments will be performed in two separate protocols: 1) to evaluate the kinetics of distribution in brain tissue, the drugs, labeled with fluorophores, will be administered at doses of 1 or 5 mg / kg, 30 minutes, 2 hours or 4 hours, by oral or intravenous route, or 2) the drugs will be administered, once a day, by oral or intraperitoneal route, for 10 days, for evaluation of tumor development or for assessment of microcirculatory parameters. Intravital microscopy studies will be performed to evaluate the distribution of the nanocapsules in the microcirculation of the brain tissue, as well as leukocyte-endothelial interactions, leukocyte-platelet and platelet-endothelium, thrombus formation, and hemorrhagic areas in vessels of the cerebral microcirculation. Additionally, the effect of drugs on the integrity of the blood-brain barrier will be determined by ex vivo assay (solution of Evans 'blue') and therapeutic efficacy of the compounds will be evaluated by measuring the kinetics of tumor formation in the brain, using histological and imunohistochemistry assays. Together, these assays can determine a set of in vivo and ex vivo strategies to evaluate the therapeutic activity and toxicity of nanocapsules, focusing on vectorizing of anticancer drugs. In addition, they will contribute to the knowledge of toxic actions of indomethacin and its ester ethyl nanocapsules in the microcirculatory network. It is noteworthy that intravital microscopy methodology has not been employed in Brazil for this purpose and the realization of this project will disseminate the knowledge obtained by Dr. Stephen Rodrigues during his Post-doctorate abroad (Microcirculation Laboratory, LSU Health Sciences Center, Shreveport, LA, USA) in an area relevant to therapy and drug toxicology. The Dr Sandra Farsky s laboratory has expertize in intravital microscopy studies in inflammation and clotting parameters, but has no experience in kinetic studies of nanoparticles in brain tissue. The laboratory has intravital microscopy equipment for this purpose, acquired in projects previously funded by FAPESP. Thus, the inclusion of Dr. Stephen Rodrigues will extend the approach of studies at the Laboratory of Experimental Toxicology, coordinated by Dr Sandra Farsky.

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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)
CLARET PEREIRA, NATALIA RUBIO; LOIOLA, RODRIGO AZEVEDO; RODRIGUES, STEPHEN FERNANDES; DE OLIVEIRA, CATIUSCIA P.; BUTTENBENDER, SABRINA L.; GUTERRES, SILVIA S.; POHLMANN, ADRIANA R.; FARSKY, SANDRA H. Mechanisms of the effectiveness of poly(epsilon-caprolactone) lipid-core nanocapsules loaded with methotrexate on glioblastoma multiforme treatment. INTERNATIONAL JOURNAL OF NANOMEDICINE, v. 13, p. 4563-4573, 2018. Web of Science Citations: 3.
RODRIGUES, STEPHEN F.; FIEL, LUANA A.; SHIMADA, ANA L.; PEREIRA, NATALIA R.; GUTERRES, SILVIA S.; POHLMANN, ADRIANA R.; FARSKY, SANDRA H. Lipid-Core Nanocapsules Act as a Drug Shuttle Through the Blood Brain Barrier and Reduce Glioblastoma After Intravenous or Oral Administration. JOURNAL OF BIOMEDICAL NANOTECHNOLOGY, v. 12, n. 5, p. 986-1000, MAY 2016. Web of Science Citations: 25.
RODRIGUES, STEPHEN F.; GRANGER, D. NEIL. Blood cells and endothelial barrier function. TISSUE BARRIERS, v. 3, n. 1-2, SI 2015. Web of Science Citations: 74.
RODRIGUES, S. F.; GRANGER, D. N. Leukocyte-mediated Tissue Injury in Ischemic Stroke. Current Medicinal Chemistry, v. 21, n. 19, p. 2130-2137, JUN 2014. Web of Science Citations: 11.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.