Evaluation of the antitumor effects of the DODAC/synthetic phosphoethanolamine liposomal formulation in a model of hepatocellular

• Grant number: 15/02950-1
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: July 01, 2015
• End date: June 30, 2017
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Durvanei Augusto Maria
• Grantee: Arthur Cassio de Lima Luna
• Host Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

In vitro study performed by our group demonstrated the efficacy of DODAC/PHO-S (dioctadecyldimethylammonium chloride/synthetic phosphoethanolamine) liposomal formulation on inhibition of cell proliferation and induced toxicity on B16F10 murine melanoma cells and Hepa1c1c7 murine hepatocellular carcinoma. Preliminary results obtained by our group (paper submitted for publication), demonstrated that Hepa1c1c7 cells exhibited greater sensitivity to treatment with the liposomal formulation. This probably may be correlated with the interaction of the DODAC with lipid receptors of these cells, enabling greater availability of DODAC carrying with very quickly PHO-S to cell membrane. Thus, this project aims to evaluate the efficacy of DODAC/PHO-S liposomal formulation on the induction of cytotoxic in hepatocellular carcinoma in an experimental model of C57BL/6 mice, aiming for the future use this formulation for treatment of liver cancer. For assay, an orthotropic animal model of hepatocellular carcinoma will be created by inoculation with murine hepatocellular carcinoma Hepa1c1c7 cells, via intrahepatic, at a concentration of 106. The animals will be euthanized at intervals at 7, 15, 30 and 40 days after the inoculation of tumor cells, and the organs will be processed for histopathological analysis, in order to verify tumor establishment. This experimental model has not yet been described in the literature (attachment preliminary data). After diagnosis of the tumor establishment, at 20 days after inoculation, the animals will be treated with DODAC/PHO-S (1:1) liposomal formulation 35 mg/kg, administered intravenously and intrahepatic, injection given at 48 hours intervals, for 20 days. Will be carried out weekly the measurement of weight and the collect blood samples by retro-orbital bleeding for haematological and biochemical analysis. After the end of protocol treatment, histopathological examination of the organs will be performed in the control animals and animals treated, and the immunohistochemical assay for protein expression levels: glutamine synthetase, surviving and of the receptor VEGF-R1 e R2. Tumor fragments will be digested by collagenase and the aliquots of cells will be used to quantify the expression of the following proteins: caspase 3, 8 and 7 actives, cytochrome c, p53, p27, p21, VEGF-R1, Bcl-2, Bad, Bax e tBid by cytometry flow and RT-PCR. Thus, the implementation this project will provide indispensable information for technology development of delivery systems for treating hepatocellular carcinoma, in order to maximize the induction of cytotoxicity in this tumor and reduce unwanted side effects. (AU)

Scientific publications

(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)

DE LIMA LUNA, ARTHUR CASSIO; VIEGAS SARAIVA, GREICE KELLE; RIBEIRO FILHO, OTAVIANO MENDONCA; CHIERICE, GILBERTO ORIVALDO; NETO, SALVADOR CLARO; CUCCOVIA, IOLANDA MIDEA; MARIA, DURVANEI AUGUSTO. Potential antitumor activity of novel DODAC/PHO-S liposomes. INTERNATIONAL JOURNAL OF NANOMEDICINE, v. 11, p. 1577-1591, 2016. (15/02950-1)

DE LIMA LUNA, ARTHUR CASSIO; VIEGAS SARAIVA, GREICE KELLE; CHIERICE, GILBERTO ORIVALDO; HESSE, HENRIQUE; MARIA, DURVANEI AUGUSTO. Antiproliferative and proapoptotic effects of DODAC/synthetic phosphoethanolamine on hepatocellular carcinoma cells. BMC PHARMACOLOGY & TOXICOLOGY, v. 19, JUL 11 2018. (15/02950-1)

DE LIMA LUNA, ARTHUR CASSIO; VIEGAS SARAIVA, GREICE KELLE; RIBEIRO FILHO, OTAVIANO MENDONCA; CHIERICE, GILBERTO ORIVALDO; NETO, SALVADOR CLARO; CUCCOVIA, IOLANDA MIDEA; MARIA, DURVANEI AUGUSTO. Potential antitumor activity of novel DODAC/PHO-S liposomes. INTERNATIONAL JOURNAL OF NANOMEDICINE, v. 11, p. 15-pg., 2016-01-01. (15/02950-1)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

LUNA, Arthur Cassio de Lima. Potential antitumor of the DODAC/PHO-S liposomal formulation in the model of hepatocellular carcinoma. 2017. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina (FM/SBD) São Paulo.