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  • MDL 800 The expression of GLUT receptors

    2022-05-19

    The expression of GLUT receptors throughout the body could be considered a potential source for off-target effects even for engineered glucose-conjugated nanomedicines, as there are at least 12 types of GLUT transporters in the body, including GLUT1 in erythrocytes and the blood-brain barrier, as well as ubiquitously expressed for basal-level glucose uptake, GLUT2 in hepatocytes, intestines, kidney and β-pancreatic cells, GLUT3 in neurons, sperm and circulating white blood cells, and insulin-triggered GLUT4 in adipocytes and muscles [14,34]. Nevertheless, the interaction of the micelles with GLUTs expressed on interstitial cells may be restricted, as the relatively large size of polymeric micelles prevents their extravasation into healthy tissues due to the upper limits of the pore size for transvascular flow across the different endothelial layers [43]. For example, 1-nm upper limit for non-sinusoidal non-fenestrated blood capillaries, such as those in the brain, 5-nm for MDL 800 having clefts lined with macula occludens junctions, such as the capillaries of skeletal muscle, 6–12 nm for non-sinusoidal fenestrated blood capillaries with diaphragmed fenestrae, such as the vessels in exocrine glands, and 15-nm for capillary walls of non-sinusoidal fenestrated capillaries with open fenestrae, such as the kidney glomeruli [43]. The comparable levels of Gluc-25%-CDDP/m and CDDP/m in plasma and organs verify the aforesaid observation, and demonstrate that the GLUT1 targeting ability of the micelles did not lead to an off-target distribution. Moreover, the Gluc-25%-CDDP/m selectively accumulated in tumor, as confirmed by the AUC ratio between the OSC19 tumors and the organs, which was always higher than 1. Such high tumor selectivity of Gluc-25%-CDDP/m allowed promoting the therapeutic efficacy without toxicity. The GLUT1 on endothelial cells controls the passage of glucose through vascular barriers, such as the blood-brain barrier or the blood-retinal barrier [20,21,44]. Our immunofluorescence study also showed the presence of GLUT1 on the malignant vasculature, conceivably accounting for the import of glucose into the tumors. On the other hand, it should be pointed that, while GLUT1 can readily deliver small glucose molecules through facilitated diffusion, large macromolecular glucose-conjugates cannot pass across GLUT1. Nevertheless, our previous report showed that the extravasation of glucose-installed micelles through the blood-brain barrier into the brain parenchyma was significantly enhanced by the regulation of the subcellular localization of GLUT1 by glycaemic control, as follows: after a period of fasting, high-levels of GLUT1 were located on the luminal side of brain endothelial cells, which enhanced the binding to glucose-installed micelles circulating in the bloodstream. Then, an intraperitoneal administration of glucose triggered the recycling of the GLUT1 to the abluminal side of the brain endothelial cells, carrying the glucose-installed micelles into the brain parenchyma [45]. On the other hand, in the case of OSC-19 and U87MG tumors, Gluc-25%-CDDP/m were translocated into the tumor interstitium without the assistance of a glycaemic control, while the brain accumulation of the micelles remained low, excluding potential toxicities to the brain at normal conditions without fasting and glycemic control. This GLUT1-facilitated transport in tumors could be associated with the increased levels and subcellular localization of GLUT1 on the endothelial cells of tumors due to the alterations in metabolic homeostasis, such as nutrient or oxygen deprivation, or extracellular signals promoting cell growth and proliferation [[46], [47], [48], [49], [50], [51], [52], [53]]. For example, hypoxia, which is a hallmark of malignancy, has been shown to increase GLUT1 expression in the luminal side of endothelial cells [[46], [47], [48], [49]]. Moreover, the GLUT1 position on cells is being continuously adjusted according to metabolic demands, shifting from internal vesicular compartments to the cell surfaces, and vice versa [[50], [51], [52], [53]]. Such perturbations in the GLUT1 expression, activity and location due to the altered metabolism may also explain the selective and rapid enhancement of the accumulation of Gluc-25%-CDDP/m into the tumors compared to the healthy organs.