Capillary endothelial but not lymphatic function is restored under rosiglitazone in Zucker diabetic fatty rats.

If thiazolidinediones have shown beneficial effects on macrovascular endothelial function, their effects on microcirculation and lymphatic function are not well documented. The aim of the study was to assess the effect of rosiglitazone on interstitial albumin retention and lymphatic function in Zucker Diabetic Fatty (ZDF) rats. Three series of 9-14 rats were studied: Lean (fa/?) controls, ZDF (Gmi-fa/fa) rats and ZDF rats treated with rosiglitazone from 8 to 26 weeks of age (ZDF-ROSI). Albumin retention and lymphatic uptake of interstitial albumin (LF/HF ratio) were evaluated on hindquarters with a noninvasive isotopic test using technetium-labelled albumin. Vascular Endothelial Growth Factor (VEGF) was measured. At week 25, albumin retention was markedly higher in ZDF rats (9.9+/-1.0%) than in control rats (1.0+/-0.8%, p<0.001), but did not differ significantly between the ZDF-ROSI group (2.5+/-1.5%) and the control group. LF/HF ratio was similarly increased in the ZDF group (1.14+/-0.07%) and the ZDF-ROSI group (1.07+/-0.04%) as compared to control rats (0.65+/-0.04%; p<0.001 for both). We can deduce that the prevention of the increase of albumin retention under rosiglitazone results from a decrease in the capillary filtration of albumin. VEGF levels were 7.1+/-1.5, 7.3+/-1.9, 3.5+/-1.6 pg/mL in the control, ZDF and ZDF-ROSI groups, respectively (p=0.23). In ZDF rats, rosiglitazone prevents interstitial albumin retention and the increase in capillary filtration of albumin. However lymphatic function is still impaired and might contribute to oedema.

Quercetin, Siamois 1 and Siamois 2 induce apoptosis in human breast cancer MDA-mB-435 cells xenograft in vivo.

We sought to investigate the apoptosis-inducing activities of quercetin, Siamois 1, and Siamois 2 against invasive estrogen-receptor negative MDA-MB 435 cells xenografted in athymic nude mice. This study clearly demonstrated that these compounds exhibited apoptosis-inducing activities in cell culture system. Quercetin (20 microg/mL), Siamois 1 (100 microg/mL), and Siamois 2 (200 microg/mL) can induce apoptotic cell death by 40 +/-5%, 44 +/- 14 %, and 31 +/- 13 %, respectively. Two-fold of IC50 of these compounds were clearly found to induce apoptosis in breast tumor tissue which can be determined by 99mTc-Annexin V scintigraphy and histological staining. This is the first report that the apoptosis-inducing effects of quercetin, Siamois 1 and Siamois 2 on the MDA-MB 435 cell in vitro were effectively extrapolated to the in vivo situation. These compounds might be considered as a simple dietary supplement and with further clinical investigation for their use as a nutrition-based intervention in breast cancer treatment.

In vitro evaluation and biodistribution of a 99mTc-labeled anti-VEGF peptide targeting neuropilin-1.

Neuropilins (NRP) are receptors of angiogenic vascular endothelial growth factor (VEGF). Their overexpression was correlated with tumor angiogenesis and growth suggesting that their specific targeting could provide a new marker of tumor progression. Here, we observed in vitro that new (99m)Tc-labeled derivative of anti-VEGF heptapeptide, ATWLPPR, binds to NRP1 but not to NRP2. Our radiotracer is stable up to 24 h in human serum and in cysteine challenge. But, its too low affinity and too fast extraction indicate further improvement to give a successful imaging of tumor in vivo.

In vitro and in vivo study of 99mTc-MIBI encapsulated in PEG-liposomes: a promising radiotracer for tumour imaging.

Encapsulation of technetium-99m sestamibi ((99m)Tc-MIBI) in polyethyleneglycol-liposomes ((99m)Tc-MIBI-PEG-liposomes) could extend the duration of its circulation in blood and alter its biodistribution, enabling its concentration in tumours to be increased. An original method to encapsulate (99m)Tc-MIBI in PEG-liposomes is described. The (99m)Tc-MIBI-PEG-liposomes were compared with free (99m)Tc-MIBI with respect to (a) tumour availability (b) ability to distinguish between chemotherapy-sensitive and -resistant cells and (c) uptake ratio in tumour imaging. PEG-liposomal systems composed of distearoylphosphatidylcholine/cholesterol/PEG(2000)-distearoyl phosphatidylethanolamine and lissamine-rhodamine B-labelled liposomes were used. The encapsulation of (99m)Tc-MIBI in liposomes was achieved using the K(+) diffusion potential method. We compared the uptake of free versus encapsulated (99m)Tc-MIBI by sensitive and resistant erythroleukaemia (K562) and breast tumour (MCF-7ras) cells. To assess the internalisation of these liposomes into cells, rhodamine B-labelled PEG-liposomes were used and visualised by fluorescence microscopy. Biodistribution and imaging characteristics of encapsulated and free radiotracer were determined in rats and tumour-bearing nude mice. The efficiency of (99m)Tc-MIBI encapsulation in PEG-liposomes was 50+/-5%. Use of (99m)Tc-MIBI-PEG-liposomes did not impair the ability of this tracer to distinguish between chemotherapy-sensitive and -resistant tumour cells; the percentage of radioactivity accumulated in the sensitive K562 cells was 1.24+/-0.04%, as compared with 0.41+/-0.04% in the resistant K562 cells. One hour post injection in rats, PEG-liposomes showed a ten times higher activity in blood than free (99m)Tc-MIBI, whereas activity of free (99m)Tc-MIBI in kidneys and bladder was markedly higher than that of encapsulated (99m)Tc-MIBI, indicating faster clearance of the free radiotracer. In the (MCF7-ras)-bearing nude mice, PEG-liposome uptake in tumour was two times that of free (99m)Tc-MIBI. Summarising, the (99m)Tc-MIBI-PEG-liposomes demonstrated a longer blood circulation time, enabled distinction between chemotherapy-sensitive and -resistant cells and improved tumour to background contrast in in vivo imaging. (99m)Tc-MIBI-PEG-liposomes therefore show promising potential for tumour imaging.