Synthesis of lipid nanocarriers for modulation of tumor and immunocompetent cells

Abstract

Cancer is the most recurrent chronic disease in the world. Human Hepatocellular Carcinoma (HCC) is the second type of Cancer with highest number of deaths in the world and their frequency of relapses and metastasis require the development of new diagnostic and therapeutic approaches. Neoplastic cells have the ability to evade immune surveillance, modulating tumor microenvironment, to favor tumor progression in the body. Nanocomposites can be used to prevent the expression of immunosuppressive proteins and cytokines, increasing the activity of the main mechanisms of cellular immunity. This project aims to develop a nanocarrier to transport immunomodulatory agents into Cancer and immunocompetent cells. Nanoparticles will be synthesized with lipids and proteins from plasma membrane of neoplastic cells to deliver a large amount of antigenic material to professional Antigen-Presenting Cells (APC). To establish a pro-inflammatory response, lipid nanoparticles will be incorporated with monophosphoryl lipid A and oligonucleotide sequence (siRNA or LNA) to silence a specific oncogene. Following, nanoparticles will be exposed to HCC cells, peripheral blood monocytes from healthy donors, Dendritic Cells (DCs) and macrophages generated in vitro. The nanocarriers will be tested for: a) nanoparticle internalization into cancer and immunocompetent cells; b) immunomodulatory activity, observing the expression of cell surface markers and cytokine production, and c) cytotoxicity of nanocarriers. Uptake will be analyzed by fluorescence microscopy and cytotoxicity by flow cytometry. We aim at increasing the immunogenicity of the tumor cell, upon positively modulating the action of the antigen-presenting cells (APCs). (AU)