Metabolism of a cholesterol-rich microemulsion (LDE) in patients with multiple myeloma and a preliminary clinical study of LDE as a drug vehicle for the treatment of the disease

Hungria, Vânia; Latrilha, Maria C.; Rodrigues, Debora Garcia; Bydlowski, Sérgio Paulo; Chiattone, Carlos S.; Maranhão, Raul C.

doi:10.1007/s00280-003-0692-y

Cited by 73 publications

(57 citation statements)

References 41 publications

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“…Apo E is recognized by the LDL receptors on the cell membrane, and LDE can thereby be internalized via the LDL receptor-mediated endocytic pathway. 8,9 The nanoparticles concentrate in inflamed, neoplastic, and other rapidly proliferating tissues; because in this, there is an overexpression of LDL receptors. 10,11 Use of LDE as a vehicle for methotrexate (MTX) increased cell uptake of the drug severalfold.…”

Section: Introductionmentioning

confidence: 99%

Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats

Maranhão¹,

Guido²,

Lima³

et al. 2017

IJN

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Purpose Acute myocardial infarction (MI) is accompanied by myocardial inflammation, fibrosis, and ventricular remodeling that, when excessive or not properly regulated, may lead to heart failure. Previously, lipid core nanoparticles (LDE) used as carriers of the anti-inflammatory drug methotrexate (MTX) produced an 80-fold increase in the cell uptake of MTX. LDE-MTX treatment reduced vessel inflammation and atheromatous lesions induced in rabbits by cholesterol feeding. The aim of the study was to investigate the effects of LDE-MTX on rats with MI, compared with commercial MTX treatment. Materials and methods Thirty-eight Wistar rats underwent left coronary artery ligation and were treated with LDE-MTX, or with MTX (1 mg/kg intraperitoneally, once/week, starting 24 hours after surgery) or with LDE without drug (MI-controls). A sham-surgery group (n=12) was also included. Echocardiography was performed 24 hours and 6 weeks after surgery. The animals were euthanized and their hearts were analyzed for morphometry, protein expression, and confocal microscopy. Results LDE-MTX treatment achieved a 40% improvement in left ventricular (LV) systolic function and reduced cardiac dilation and LV mass, as shown by echocardiography. LDE-MTX reduced the infarction size, myocyte hypertrophy and necrosis, number of inflammatory cells, and myocardial fibrosis, as shown by morphometric analysis. LDE-MTX increased antioxidant enzymes; decreased apoptosis, macrophages, reactive oxygen species production; and tissue hypoxia in non-infarcted myocardium. LDE-MTX increased adenosine bioavailability in the LV by increasing adenosine receptors and modulating adenosine catabolic enzymes. LDE-MTX increased the expression of myocardial vascular endothelium growth factor (VEGF) associated with adenosine release; this correlated not only with an increase in angiogenesis, but also with other parameters improved by LDE-MTX, suggesting that VEGF increase played an important role in the beneficial effects of LDE-MTX. Overall effects of commercial MTX were minor, and did not improve LV function or infarction size. Both treatments did not induce any toxicity. Conclusion The remarkable improvement in heart function and reduction in infarction size achieved by LDE-MTX supports future clinical trials.

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Section: Introductionmentioning

confidence: 99%

Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats

Maranhão¹,

Guido²,

Lima³

et al. 2017

IJN

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“…As most cancer cell lines show LDL receptor upregulation, LDE can be used as a vehicle to direct antineoplastic drugs to those cells, as demonstrated in breast and ovary carcinoma tissues 7,8 as well as in hematologic cancers such as acute myelocytic leukemia and multiple myeloma. 9,10 Association to LDE of drugs such as carmustine, etoposide, and paclitaxel pronouncedly reduces the toxicity of those agents while preserving or even increasing the antineoplastic activity, as shown in tumor-implanted rats and mice. [11][12][13] In a subsequent study, we showed that LDE can also concentrate in the lesioned aortas of cholesterol-fed rabbits after injection into the blood circulation.…”

mentioning

confidence: 99%

“…15 Reduction of toxicity of chemotherapeutic agents by associating them to LDE was confirmed at clinical level. In trials enrolling patients with advanced cancers treated with LDE-carmustine, 10 LDE-paclitaxel, 16 and LDE-etoposide, 17 the toxicity of high-dose treatments was minimal or absent.…”

mentioning

confidence: 99%

Reduction of atherosclerotic lesions in rabbits treated with etoposide associated with cholesterol-rich nanoemulsions

Tavares¹,

Freitas²,

Diament³

et al. 2011

IJN

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Objectives Cholesterol-rich nanoemulsions (LDE) bind to low-density lipoprotein (LDL) receptors and after injection into the bloodstream concentrate in aortas of atherosclerotic rabbits. Association of paclitaxel with LDE markedly reduces the lesions. In previous studies, treatment of refractory cancer patients with etoposide associated with LDE had been shown devoid of toxicity. In this study, the ability of etoposide to reduce lesions and inflammatory factors in atherosclerotic rabbits was investigated. Methods Eighteen New Zealand rabbits were fed a 1% cholesterol diet for 60 days. Starting from day 30, nine animals were treated with four weekly intravenous injections of etoposide oleate (6 mg/kg) associated with LDE, and nine control animals were treated with saline solution injections. Results LDE-etoposide reduced the lesion areas of cholesterol-fed animals by 85% and intima width by 50% and impaired macrophage and smooth muscle cell invasion of the intima. Treatment also markedly reduced the protein expression of lipoprotein receptors (LDL receptor, LDL-related protein-1, cluster of differentiation 36, and scavenger receptor class B member 1), inflammatory cytokines (interleukin-1β and tumor necrosis factor-α), matrix metallopeptidase-9, and cell proliferation markers (topoisomerase IIα and tubulin). Conclusion The ability of LDE-etoposide to strongly reduce the lesion area and the inflammatory process warrants the great therapeutic potential of this novel preparation to target the inflammatory-proliferative basic mechanisms of the disease.

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“…Deste modo, não só valores baixos de LDL, como também aumento da expressão dos receptores de LDL e maior captação desta lipoproteína pelas células neoplásicas, já foram demonstrados em doentes portadores de leucemia mielóide aguda, 15,16,17 doenças mieloproliferativas, 18 mieloma múlti-plo, 19 adenocarcinoma endometrial e carcinomas de cérvix, 20 mama, 21 próstata, 22 ovário, 23 vesícula biliar 24 e pulmão. 25 O mecanismo proposto para explicar estas observações é a maior remoção do colesterol da LDL plasmática para atender ao aumento da síntese de novas membranas das células neoplásicas.…”

Section: O Perfil Lipídico Nas Hemoglobinopatias E Talassemiasunclassified

Alterações do perfil lipídico nas anemias

Naoum¹

2005

Rev. Bras. Hematol. Hemoter.

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Metabolism of a cholesterol-rich microemulsion (LDE) in patients with multiple myeloma and a preliminary clinical study of LDE as a drug vehicle for the treatment of the disease

Abstract: Because it targets multiple myeloma and, when associated with an antineoplastic agent, produces therapeutic responses in patients with fewer side effects, LDE has the potential for use as a drug vehicle in the treatment of the disease.

Cited by 73 publications

References 41 publications

Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats

Methotrexate carried in lipid core nanoparticles reduces myocardial infarction size and improves cardiac function in rats

Reduction of atherosclerotic lesions in rabbits treated with etoposide associated with cholesterol-rich nanoemulsions

Alterações do perfil lipídico nas anemias

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