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Cerebral edema, a major complication of tumors in the brain, is the result of an alteration in the blood-brain barrier (B-BB). The vascular ultrastructural changes that underlie edema formation have been described in a variety of tumors. Interendothelial junction abnormalities, fenestrations, and large numbers of tubulo-vesicular profiles in the tumor vascular endothelium have been presumed to represent permeability routes that permit the escape of serum constituents into the tumor, from where they flow into the surrounding brain. Descriptive studies do not provide information on the relative frequency of these presumptive permeability routes. In the study reported here we have quantified ultrastructural features associated with the B-BB in the vessels of an experimental glioma in rat. We found that approximately 60% of the tumor vessel profiles have junctional abnormalities and 30% have one or more fenestrations. The density of tubulo-vesicular profiles, however, was not increased. In addition, tumor vessel walls were thicker than normal vessels of the same caliber and the mitochondrial density was in the range of that for non-barrier vessels. Vessels in peritumoral regions were not altered in any of the parameters measured.

Liposomes have been proposed as carriers for the delivery of molecules to cells. They have been shown to enhance the efficacy of encapsulated drugs, prolonging the circulation time and reducing side effects. Moreover, the targeting of liposomes to desirable sites has been attempted. 1,2) In addition, a number of attempts have been made to develop functional liposomes, which can regulate the release of drugs responding to various stimuli, such as pH, [3][4][5][6] light 7,8) and temperature. 9-15)The liposomes injected into blood would be opsonized by serum components, and rapidly taken up by the reticuloendothelial system (RES) including the liver and spleen. [16][17][18][19][20] This is a major problem for researchers, because it is a significant disadvantage for the delivery of drugs to non-RES tissues. Moreover, some serum components have a destabilizing effect upon lipid vesicles and thereby cause leakage of liposomal contents. For example, high-density lipoprotein (HDL) is known to cause the disintegration of liposomes. 21,22) Yatvin et al. and Weinstein et al. reported an unique approach to controlling the release of drugs using temperaturesensitive liposomes in conjunction with local hyperthermia.9-11) The barrier efficiency of the membrane abruptly decreases near the gel-to-liquid crystalline phase transition temperature (T m ) of the phospholipid membrane. The temperature-sensitive liposomes have been designed to release a drug in response to local hyperthermia, during which a tumor was heated at temperatures of 41 to 45°C. Other strategies have been used for the production of temperature-sensitive liposomes. One example is the use of polymers, which are attached to the liposome to exhibit temperature-sensitivity and cause release of the internal content above a certain temperature. 14,15) In the development of the liposome, pharmaceutical scientists have been confronted with two difficulties. The first is how to prolong circulation time. Recently, the liposome surface has been modified with GM1 ganglioside 23) and polyoxyethylene derivatives, 24,25) which have some ability to escape the RES. The second is the problem regarding the stability of liposomes in systemic circulation after injection. In general, it is favorable for a drug delivery system (DDS) to have liposomes that are stable in the blood circulation, especially for chemotherapy and gene therapy. In addition, when trying to develop stimulus-sensitive liposomes, one should consider the influence of the serum components on the function of liposomes. Liu and Huang have observed that DOPEbased pH-sensitive liposomes lost their pH-sensitivity in the presence of serum. 26)Anionic lipids are frequently used in preparing liposomes for drug delivery. In the fluid state, negatively charged liposomes composed of phosphatidylglycerol (PG) interacted with serum components and caused an increase in the leakage of the encapsulated drug. 27) Therefore, it is necessary to investigate the effects of serum components on the temperature-dependent release propert...

Normal blood vessels invading a growing neoplasm undergo dramatic changes in morphology. Whether vessel characteristics are dictated entirely by the tumor, or from developmental restrictions in normal vessels from which tumor vessels originate is not known. To address this question we challenged two morphologically different types of capillaries (brain and muscle) with the same tumor environment (C6 astrocytoma), and quantified the invading vessel morphology. A vascular spheroids of C6 astrocytoma cells were implanted singly into rat cerebral cortex or iliacus muscle. Microvessels from the tumor, peritumoral tissue and control tissue were examined ultrastructurally and quantified. Tumor vessels differed significantly from host vessels but not from each other, regardless of implantation site. Neoplastic vessels were thick-walled relative to normal host vessels, had low densities of mitochondria and vesicular structures, and had both fenestrations and enlarged junctional clefts characteristic of highly permeable vessels. Control brain vessels were typically thin-walled, had a high density of mitochondria, a low density of endothelial vesicles and continuous tight junctions. Control muscle vessels were thin-walled with a low density of mitochondria, high density of vesicles and junctional zones with occasional enlarged clefts. Peritumoral vessel morphology was intermediate between that of tumor and the corresponding control tissue. We propose that C6 astrocytoma cells influence invading endothelial cells to develop a permeable phenotype radically different from host tissue endothelium, and host vessel phenotype does not influence tumor vessel morphology.

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The in vivo elimination and tissue distribution (2 h after administration) of various types of formulations of alpha-tocopherol as a model drug were examined in rats. An organic cosolvents formulation of alpha-tocopherol (alpha-tocopherol/EtOH/polyethylene glycol 400) was rapidly removed from the blood circulation, the ratio of the distributed alpha-tocopherol was 20% in the lungs, about 70% in the liver and about 10% in the spleen. The main reason for this was considered to be the appearance of droplets more than 10 microns in diameter in the blood. Elimination of the micelle formulation using Brij58 from the blood was the most rapid, followed by Tween80 and HCO60. This order is thought to be due to the difference in the polyoxyethylene group among these surfactants. In liposome formulations, liposomes having a diameter of about 80 nm were the most stable in the blood circulation, and alpha-tocopherol was distributed in the reticuloendothelial system (RES) in the smallest ratio. The uptake of liposomes by the spleen and lungs depended on the liposome size. The uptake by the liver was in the decreasing order of 28 nm >> 42 nm, 151 nm, 195 nm, 3656 nm > 106 nm > 75 nm. The 100 nm lipid emulsion was eliminated from the blood more rapidly than the 100 nm liposome formulation.