LDL particle size: an important drug target?

Rajman, Iris; Eacho, Patrick I.; Chowienczyk, Phil; Ritter, James M.

doi:10.1046/j.1365-2125.1999.00991.x

Cited by 58 publications

(53 citation statements)

References 82 publications

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“…39 In comparison, the molecular weight of our MNT is approximately 70 kDa, and that of low-density lipoprotein is about 3000 kDa. 40 Leunig et al, 41 who investigated tumor accumulation of different porphyrin-like photosensitizers, showed that the enhanced permeability and retention effect appears to be the most probable reason for the tumor selectivity of this type of photosensitizer. Therefore, qualitatively, free photosensitizer in tumor vessels and photosensitizer transported by MNT may be considered as similar in terms of enhanced permeability and retention effect, and perhaps even more favorable for the free photosensitizer.…”

Section: Discussionmentioning

confidence: 99%

Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery

Slastnikova

Rosenkranz²,

Gulak³

et al. 2012

IJN

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Background: Modular nanotransporters (MNT) are recombinant multifunctional polypeptides created to exploit a cascade of cellular processes, initiated with membrane receptor recognition to deliver selective short-range and highly cytotoxic therapeutics to the cell nucleus. This research was designed for in vivo concept testing for this drug delivery platform using two modular nanotransporters, one targeted to the α-melanocyte-stimulating hormone (αMSH) receptor overexpressed on melanoma cells and the other to the epidermal growth factor (EGF) receptor overexpressed on several cancers, including glioblastoma, and head-and-neck and breast carcinoma cells. Methods: In vivo targeting of the modular nanotransporter was determined by immunofluorescence confocal laser scanning microscopy and by accumulation of 125 I-labeled modular nanotransporters. The in vivo therapeutic effects of the modular nanotransporters were assessed by photodynamic therapy studies, given that the cytotoxicity of photosensitizers is critically dependent on their delivery to the cell nucleus.Results: Immunohistochemical analyses of tumor and neighboring normal tissues of mice injected with multifunctional nanotransporters demonstrated preferential uptake in tumor tissue, particularly in cell nuclei. With 125 I-labeled MNT{αMSH}, optimal tumor:muscle and tumor:skin ratios of 8:1 and 9.8:1, respectively, were observed 3 hours after injection in B16-F1 melanoma-bearing mice. Treatment with bacteriochlorin p-MNT{αMSH} yielded 89%-98% tumor growth inhibition and a two-fold increase in survival for mice with B16-F1 and Cloudman S91 melanomas. Likewise, treatment of A431 human epidermoid carcinoma-bearing mice with chlorin e 6 -MNT{EGF} resulted in 94% tumor growth inhibition compared with free chlorin e 6 , with 75% of animals surviving at 3 months compared with 0% and 20% for untreated and free chlorin e 6 -treated groups, respectively. Conclusion:The multifunctional nanotransporter approach provides a new in vivo functional platform for drug development that could, in principle, be applicable to any combination of cell surface receptor and agent (photosensitizers, oligonucleotides, radionuclides) requiring nuclear delivery to achieve maximum effectiveness.

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Section: Discussionmentioning

confidence: 99%

Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery

Slastnikova

Rosenkranz²,

Gulak³

et al. 2012

IJN

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“…Hypolipidemic treatment is able to alter LDL subclass distribution (10). Medications with triglyceride-lowering effects cause a shift from smaller, denser to larger, more buoyant particles and this may be explained by the fact that a reduced availability of triglyceride-rich particles leads to a reduction in the production of small, dense LDLs.…”

Section: Atherogenic Lipoprotein Phenotype and Hypolipidemic Treatmentsmentioning

confidence: 99%

Lipid Triad or Atherogenic Lipoprotein Phenotype: A Role in Cardiovascular Prevention?

Rizzo

Berneis²

2005

JAT

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The term "lipid triad" or "atherogenic lipoprotein phenotype" has been introduced to describe a common form of dyslipidemia, characterized by three lipid abnormalities: increased plasma triglyceride levels, decreased HDL-cholesterol concentrations and the presence of small, dense LDL particles. It has been suggested that the clinical importance of the atherogenic lipoprotein phenotype probably exceeds that of LDLcholesterol, because many more patients with coronary artery disease are found to have this trait than hypercholesterolaemia. There is a body of evidence that therapies effective against plasma HDL-cholesterol and triglycerides are associated with a strong reduction of cardiovascular risk; in addition, hypolipidemic treatment is able to increase LDL particle size and this increment correlates with regression of coronary stenosis. Recently, the Coordinating Committee of the National Cholesterol Education Program suggested that very high-risk patients may benefit from stronger lipidlowering measures, a category of individuals that includes those with the atherogenic lipoprotein phenotype. Since the therapeutical modulation of each of the three components of the lipid triad is associated with a strong reduction in the risk of cardiovascular events, LDL size measurement may be extended as much as possible to patients at high risk of cardiovascular diseases.J Atheroscler Thromb, 2005; 12: 237-239.

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“…Enhanced atherosclerosis could occur by a variety of mechanisms. 16 In several studies, once other lipid values were accounted for, 17,18 or once apoB (atherogenic particle number) was lowered to goal, 12 LDLPS did not convey independent risk information. More recent observations suggest that the simple classification of small versus large size is not as beneficial as quantifying the severity of small LDLPS distribution.…”

Section: Discussionmentioning

confidence: 99%

Usefulness of low-density lipoprotein particle size measurement in cardiovascular disease prevention

et al. 2005

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SummaryBackground: Cardiovascular disease is largely explained by the traditional risk factors, but there are several novel risk factors that have been shown to predict cardiovascular morbidity. The measurement of low-density lipoprotein particle size (LDLPS) is a novel cardiovascular risk factor, yet it is unknown whether this measurement provides additional information that may influence the subsequent medical treatment of patients.Hypothesis: The measurement of LDLPS provides additional information that may influence preventive treatment for cardiovascular disease.Methods: In an observational study of 82 patients referred to a tertiary care preventive cardiology clinic, LDLPS was dichotomized as either small or large and was determined by either the NMR LipoProfile test, the Vertical Auto Profile (VAP ™ ) cholesterol test, or gradient gel electrophoresis. Lipid profiles were obtained and Framingham risk scores were calculated. Patients were stratified by Adult Treatment Panel guidelines as being at low, intermediate, or high risk.Results: The study included 56 men and 26 women with a mean age of 54 ± 11 years. In the entire cohort of 82 patients, only 31 (38%) were at non-high-density lipoprotein (HDL) goal, only 21 (26%) were at goals for both non-HDL and HDL, and only 18 (22%) were at goal for non-HDL, HDL, and triglycerides. When considering each of the risk factor strata, 19 of 43 (44%) low-risk patients were at non-HDL goal and 12 of these also had a small LDLPS. Only 8 of 18 (44%) intermediate-risk patients were at non-HDL goal and 7 of these (88%) had small LDLPS. Finally, only four high-risk pa-

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LDL particle size: an important drug target?

Cited by 58 publications

References 82 publications

Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery

Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery

Lipid Triad or Atherogenic Lipoprotein Phenotype: A Role in Cardiovascular Prevention?

Usefulness of low-density lipoprotein particle size measurement in cardiovascular disease prevention

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