Simultaneous transfer of cholesterol, triglycerides, and phospholipids to high-density lipoprotein in aging subjects with or without coronary artery disease.

OBJECTIVE: To verify whether the capacity of high-density lipoprotein (HDL) to simultaneously receive nonesterified cholesterol, triglycerides, cholesteryl esters, and phospholipids changes with aging and the presence of coronary artery disease. DESIGN: Cross-sectional study with biochemical analyses. SUBJECTS: Eleven elderly patients with coronary artery disease (74 ± 5 years) were compared with the following groups of non-coronary artery disease subjects (referred to as "healthy"): 25 young (25 ± 5 years), 25 middle-aged (42 ± 6 years), and 25 elderly subjects (75 ± 8 years). METHODS: Plasma samples were incubated with a nanoemulsion labeled with radioactive lipids; the transfer of the lipids from the nanoemulsion to the HDL was measured in chemically precipitated HDL. HDL size and paraoxonase-1 activity were also determined. RESULTS: The transfer of cholesteryl esters and phospholipids to high-density lipoprotein was significantly greater (p<0.001) in healthy elderly subjects than in the middle-aged and younger subjects. Non-esterified cholesterol and triglyceride transfer was not different among these three groups. The HDL size was significantly greater (p<0.001) in healthy elderly subjects than in the middle-aged and younger subjects. The paraoxonase-1 activity was similar among the groups. Compared with healthy elderly subjects, coronary artery disease elderly subjects had significantly less (p<0.05) transfer of non-esterified cholesterol, triglycerides, and cholesteryl esters to the HDL and a significantly smaller (p<0.05) HDL size. CONCLUSION: Because lipid transfer is enhanced in healthy elderly subjects but not in those with coronary artery disease, increasing lipid transfer to HDL may be a protective mechanism against the disease.

Simultaneous transfer of cholesterol, triglycerides, and phospholipids to high-density lipoprotein in aging subjects with or without coronary artery disease

OBJECTIVE: To verify whether the capacity of high-density lipoprotein (HDL) to simultaneously receive nonesterified cholesterol, triglycerides, cholesteryl esters, and phospholipids changes with aging and the presence of coronary artery disease. DESIGN: Cross-sectional study with biochemical analyses. SUBJECTS: Eleven elderly patients with coronary artery disease (74±5 years) were compared with the following groups of non-coronary artery disease subjects (referred to as "healthy"): 25 young (25±5 years), 25 middle-aged (42± years), and 25 elderly subjects (75±8 years). METHODS: Plasma samples were incubated with a nanoemulsion labeled with radioactive lipids; the transfer of the lipids from the nanoemulsion to the HDL was measured in chemically precipitated HDL. HDL size and paraoxonase-1 activity were also determined. RESULTS: The transfer of cholesteryl esters and phospholipids to high-density lipoprotein was significantly greater (p<0.001) in healthy elderly subjects than in the middle-aged and younger subjects. Non-esterified cholesterol and triglyceride transfer was not different among these three groups. The HDL size was significantly greater (p<0.001) in healthy elderly subjects than in the middle-aged and younger subjects. The paraoxonase-1 activity was similar among the groups. Compared with healthy elderly subjects, coronary artery disease elderly subjects had significantly less (p<0.05) transfer of non-esterified cholesterol, triglycerides, and cholesteryl esters to the HDL and a significantly smaller (p<0.05) HDL size. CONCLUSION: Because lipid transfer is enhanced in healthy elderly subjects but not in those with coronary artery disease, increasing lipid transfer to HDL may be a protective mechanism against the disease.

Plasma kinetics and uptake by the tumor of a cholesterol-rich microemulsion (LDE) associated to etoposide oleate in patients with ovarian carcinoma.

OBJECTIVES: Previously, we reported that etoposide oleate associated to a cholesterol-rich microemulsion (LDE) is taken up by malignant cells overexpressing low-density lipoprotein (LDL) receptors. The association is stable, preserves antiproliferative activity of the drug, and reduces toxicity to animals. Here, we determined in patients the plasma kinetics of LDE-etoposide oleate and verified whether the complex concentrates in ovarian carcinomas. METHODS: [(3)H]-etoposide oleate associated to LDE labeled with [(14)C]-cholesteryl oleate was intravenously injected into four ovarian carcinoma patients (50 +/- 8.7 years) 24 h before surgery. Blood samples were collected over a 24-h period to determine the radioactivity plasma decay curves, and the plasma fractional clearance rate (FCR) was calculated by compartmental analysis. Specimens of tumors and normal ovaries excised during the surgery were collected for lipid extraction and radioactive counting. RESULTS: FCRs of LDE label and of the drug were similar (0.0985 and 0.1722, respectively, P = 0.2422). [(14)C]-LDE uptake was 4.9 times and [(3)H]-etoposide oleate uptake was 4.1 times greater in the ovarian tumors than in the contralateral normal ovaries (LDE uptake, in cpm/g = 560 +/- 171 and 146 +/- 59; etoposide oleate uptake = 346 +/- 75 and 103 +/- 56, respectively). CONCLUSIONS: Most of the drug is retained in the microemulsion particles until its removal from the circulation and internalization by the cells. In addition, LDE-etoposide oleate has the ability to concentrate in malignant ovarian tissues. Therefore, the complex may be used to direct and concentrate etoposide oleate in ovarian carcinomas.

Use of a cholesterol-rich microemulsion that binds to low-density lipoprotein receptors as vehicle for etoposide.

A cholesterol-rich microemulsion (LDE) that binds to low-density lipoprotein (LDL) receptors is selectively taken up by malignant cells that overexpress those receptors and may be used as vehicle for antineoplastic agents. This study aimed to develop the association of etoposide with LDE. It was firstly observed that etoposide poorly associates with the microemulsion, therefore the experiments were performed with a lipophilic fatty acid derivative of the drug. The association of etoposide oleate with LDE was almost 100% and was tested for physical and chemical stability, as well as for cellular uptake, toxicity in mice and cytotoxic activity against a neoplastic cell line (NCI-H292). Uptake and cytotoxic activity of LDE-etoposide oleate by NCI-H292 cells was mediated by LDL receptors. The anti-proliferative activity of LDE-etoposide oleate against the neoplastic cells was smaller than that of etoposide oleate (IC50 (drug concentration required to inhibit 50% of the cell growth) = 0.48 and 0.19 mM, respectively). This difference, however, can be ascribed to the activity of the commercially used vehicle and not the drug itself because when this vehicle was added to the cultures with LDE-etoposide oleate, the IC50 decreased. On the other hand, the tolerability of LDE-etoposide oleate to mice was remarkable, such that its lethal dose (LD50) was about five-fold that of the commercial formulation (LD50 = 315 and 58 mg kg(-1), respectively). In conclusion, LDE-etoposide oleate association is stable and the cytostatic activity of the drug is preserved while its toxicity to animals is small. By diminishing the side effects and directing etoposide to neoplastic tissues, LDE may be regarded as an advance in chemotherapy with this drug.