_http://www.ajronline.org/content/185/3/763.full
One novel method that has a high degree of potential for selective delivery of chemotherapy across the blood-brain barrier is sequestration of a drug within a vehicle or carrier that could preferentially cross solely at the blood-tumor barrier. Liposomes, which are microscopic spherical vesicles constructed of phospholipid bilayers that can be designed to encapsulate contrast agents and drugs, may suit this purpose (Figs. 2A, 2B, and 2C). Considerable interest has been generated in understanding the mechanisms by which liposomes cross the blood-brain barrier under various physiologic conditions and developing methods for preferential delivery of liposomes at the tumor site. Liposomes passively target tumors in which there is disorganized vasculature [23]. This feature is more related to higher permeability than to disorganization per se [24-26]. However, specific features, such as vesicle size, chemical affinity, and thermal (or pH) sensitivities can be engineered, which provide the means for targeting liposomes for specific delivery to tumors.
One important means for modifying the target environment and increasing liposome delivery to tumors is hyperthermia [27] (Figs. 2A, 2B, and 2C). In animal models, heating to temperatures of 41-43°C increases tumor microvascular pore size and increases permeability to various substances, including ferritin, antibodies, and liposomes. The exact mechanism for this phenomenon is not known with certainty. However, a leading hypothesis is that hyperthermia may disaggregate the endothelial cell cytoskeleton, thereby decreasing size of endothelial cells and effectively increasing pore size [27]. Other actions of hyperthermia to increase permeability, such as increasing both tumor blood flow and intravascular pressure and decreasing tumor interstitial pressure, may also operate to a lesser degree. One murine study used a human tumor xenograft (SKOV-3), in which extravasation of 100-nm liposomes is not seen at normothermia (34°C) [27]. Liposome extravasation was first seen after heating to 40°C and increased after further heating to 42°C (Figs. 2A, 2B, and 2C), at which point tumor vessel hemorrhage and collapse was noted. Because temperature-sensitive liposomes can also be manufactured, the increased permeability of the blood-brain barrier to liposomes after hyperthermia raises interesting therapeutic possibilities. In preclinical models, the use of the thermally sensitive doxorubicin-containing liposome with 42°C heating resulted in a 30-fold increase in drug delivery to the tumor compared with free drug, and a fivefold increase in drug delivery compared with nonthermally sensitive liposomes [28]. It is likely that similar effects could be seen in brain tumors. For instance, hyperthermia could be locally applied to human brain tumors after IV infusion of heat-sensitive liposomes; the hyperthermia would serve to both increase permeability of the liposomes across the blood-brain barrier and also act to promote release of liposome-borne therapeutic agents into the tumor.
