Despite the concern that the BBB impairs chemotherapy entry, this barrier is selectively disrupted at the site of the malignant lesion,4,35 and therefore, the tumor will receive higher doses of systemically administered chemotherapy than the adjacent normal brain. This concept is supported by the fact that brain metastases sometimes respond to systemic chemotherapy.29,33 However, in both animal and human studies,2,9 most agents are more effective against systemic tumors than against the metastases to the brain. This is probably related to an inadequate and slow influx of compounds into brain tumors, an outcome of reduced blood flow, and increased interstitial pressure resulting from edema formation and increased intracranial pressure. Thus, the difference in drug uptake between brain metastases and their original systemic tumor is a quantitative rather than qualitative phenomenon.9 This would also imply that many brain tumors are exposed to subtherapeutic levels of chemotherapy because most agents are given as a bolus and have short distribution half-lives, resulting in a slim chance to circulate through the tumor vascular bed.
Liposome-based anticancer chemotherapy may offer the advantage of reduced systemic toxicity combined with selective drug delivery into tumor. Recent studies revealed that new formulations of small-sized (< 100 nm), longcirculating liposomes (also referred to as Stealth or sterically stabilized liposomes) appear to offer selective tumor localization.13 This localization is probably related to liposome longevity in circulation and to liposome extravasation through the abnormally permeable microvasculature of systemic tumors.10 It has also been demonstrated that the selective tumor localization of doxorubicin (DOX) encapsulated in Stealth liposomes (SLs) is associated with superior therapeutic activity over free drug activity in various systemic tumor models.10,13,34,38
The above characteristics make SLs a potentially advantageous delivery system for brain tumor chemotherapy. To date, there is no information on the behavior of SLs in experimental brain tumor models. This study evaluates the biodistribution and therapeutic efficacy of doxorubicin encapsulated in SLs (SL-DOX) in an experimental brain tumor model.
We thank Dr. A. Lossos for performing some of the preliminary evaluation of SL-DOX pharmacokinetics as part of his training program in basic sciences; we also thank Jutta Rosenthal, Ana Itzik, and Dina Tzemach for excellent technical help.
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This work was supported by grants from Liposome Technology, Inc., Menlo Park, California, The Israel Cancer Research Fund, and The Israel Ministry of Health.