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In vitro and in vivo studies with anti-electronegative LDL single chain fragments variable vectorized in nanocapsules in experimental atherosclerosis

Grant number: 12/18668-5
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): February 01, 2013
Effective date (End): September 30, 2016
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Dulcineia Saes Parra Abdalla
Grantee:Marcela Frota Cavalcante
Home Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Cardiovascular diseases are the leading cause of mortality worldwide. Atherosclerosis is on top of these diseases, being related to coronary artery disease, cerebrovascular disease and peripheral vascular disease and it is responsible for more fatalities than all types of cancer combined. Atherosclerosis is a chronic inflammatory multifactorial disease with involvement of the immune system, and performance of innate and adaptive immunity. Atherosclerosis is the result of the interaction of different cellular elements such as lymphocytes, macrophages, endothelial cells and smooth muscle cells. The low density lipoprotein (LDL) plays an important role in cardiovascular diseases, being considered a major risk factor for its development, when at high levels. A native LDL (nLDL) can undergo different types of modifications and may vary as to size, the electric charge, the structure and the composition. The electronegative low density lipoprotein [LDL (-)], a subfraction of modified native LDL plays a key role in atherosclerosis, since the modifications undergone by the particle are capable of inducing the accumulation of cholesteryl esters in macrophages and subsequent formation of foam cells. Once confirmed the involvement of the immune system in the atherogenic process, it is necessary to manipulate their action, by employing two alternatives: (i) the use of immunosuppressive drugs, or (ii) the use of passive or active immunization. Recombinant antibodies have been generated over the past decades, through genetic engineering of antibodies. Currently, besides the use of monoclonal antibodies (Mab), of limited use for their significant ability to enhance immunotoxicity by an immune response, also have been generated humanized antibodies, such as F(ab')2 and active antibody fragments, such as scFv (single chain fragment variable). These fragments can be generated in bacteria such as Escherichia coli and yeasts such as Pichia pastoris. The scFv fragments represent the smallest functional unit of the antibody and it is believed that may be used as new treatment options against the development of atherosclerosis or as a preventive factor for the appearance of the lesion. In order to increase the scFv's action efficiency in the body, nanoparticles have been developed in conjunction with these fragments. There is high probability of the system presenting low immunogenicity, suitable half-life in the circulation, better control for molecular recognition of antigen and better removal the immunocomplexes by the immune system. Given the role of LDL(-) in atherosclerosis, this project objectives to evaluate the effect of the treatment with anti-electronegative LDL scFv fragments and nanoparticles formulations containing scFv in passive immunization of knockout mice to different genes involved in the development and progression of atherosclerosis.

Matéria(s) publicada(s) na Agência FAPESP sobre a bolsa:
Nanocapsules eliminate harmful particles in cholesterol from bloodstream