Lipid core nanoparticles as vehicle for docetaxel reduces atherosclerotic lesion, inflammation, cell death and proliferation in an atherosclerosis rabbit model

Autor(es)

Meneghini, Bianca C. ^[1] ; Tavares, Elaine R. ^[1] ; Guido, Maria C. ^[1] ; Tavoni, Thauany M. ^[1] ; Stefani, Helio A. ^[2] ; Kalil-Filho, Roberto ^[1] ; Maranhao, Raul C. ^{[2, 1]}

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Med Sch Hosp, Heart Inst InCor, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Fac Pharmaceut Sci, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: VASCULAR PHARMACOLOGY; v. 115, p. 46-54, APR 2019.
• Citações Web of Science: 1

Resumo

Chemotherapeutic agents used in cancer treatment associated to nanoparticles (LDE) that mimic the composition of low-density lipoprotein and buffer their toxicity can have strong anti-atherosclerosis action, as we showed in cholesterol-fed rabbits. Here, a novel preparation of docetaxel (DTX) carried in LDE was evaluated. Eighteen rabbits were fed 1% cholesterol during 8 weeks. After the first 4 weeks, 9 animals were treated for 4 weeks with intravenous LDE-DTX (1 mg/kg/week) and 9 with LDE only (controls) once a week for 4 weeks. Animals were then euthanized and the aortas were analyzed for morphometry, immunohistochemistry and Western blot. LDE-DTX treated group showed 80% reduction of atheroma area compared to controls. LDE-DTX treatment reduced in 60% the protein expression of macrophage marker CD68 and of MCP-1 in 80%. LDE-DTX pronouncedly lowered expression of pro-inflammatory markers NF-kappa B, TNF-alpha, IL-1 beta, IL-6 and von Willebrand factor and elicited 40% reduction in cell proliferation marker PCNA. The presence of smooth muscle cells in the intima was 85% smaller than in controls. Pro-apoptotic caspase 3, caspase 9, Bax, and anti-apoptotic Bcl-2 all were reduced by LDE-DTX. Protein expression of MMP-2 and MMP-9, TGF-beta and collagen 1 and 3 were also markedly lowered by the LDE-DTX treatment. Animals showed no hematological, hepatic or renal toxicity consequent to LDE-DTX treatment. In conclusion, LDE-DTX showed a wide array of strong effects on pro-inflammatory and proliferation-promoting factors that drive the lesion development. These findings and the lack of observable toxicity indicate that LDE-DTX can be a candidate for future clinical trials. (AU)

• Processo FAPESP: 14/03742-0 - Projeto temático em medicina translacional: nanopartículas que se ligam a receptores de lipoproteínas no tratamento da aterosclerose, do infarto agudo de miocárdio, do pós-transplante de coração, do câncer e da endometriose
• Beneficiário: Raul Cavalcante Maranhao
• Modalidade de apoio: Auxílio à Pesquisa - Temático