A solid tumor comprises two major cellular components: the tumor parenchyma and the stroma; the latter incorporating the vasculature and other supporting cells. As the tumor grows, in order to meet the metabolic requirements of an expanding population of tumor cells, the pre-existing blood vessels become subject to intense angiogenic pressure. Several factors produced by tumor cells and infiltrating immune-competent effector cells in the tumor parenchyma are believed to signal the development of new capillaries from the pre-existing vessels by capillary sprouting and/or dysre-gulated intussusceptive microvascular growth. Further, in many solid tumors, endothelial cells destined to create new vessels are recruited not only from nearby vessels, but also to a significant extent from precursor cells within the bone marrow (so-called endothelial progenitor cells), a process referred to as "vasculogenesis."2

Scanning electron microscopy of microvascular corrosion casts has allowed visualization of the geometry of blood vessel architecture in solid tumors. From these studies, it has become apparent that tumor blood vessels are highly irregular and show gross architectural changes that differ from those in normal organs and from newly formed blood vessels, such as those found in wound healing and in other angiogenic sites. , For instance, the thickness of a tumor blood vessel wall is poorly correlated to its diameter. Therefore, despite the large size of some tumor vessels, the tumor blood flows is chaotic, with high flow rates in some segments and stagnation in others.1 Also, the blood flow may temporarily change direction within individual tumor vessels.

Further, the structure and organization of the endothelial cells, pericytes, and vascular basement membrane of tumor vessels are all abnormal.1,3-6 One consistent abnormality of tumor blood vessels is their high permeability to macromolecules, arising from irregularly shaped and loosely interconnected endothelial cells (where the size of fenestrae often ranges from 200 to 2000 nm) and their less frequent and intimate association with pericytes and the vascular basement membrane.1,3-5 Marked variability has been noted in endothelial permeability among different tumors, different vessels within the same tumor, and during tumor growth, regression, and relapse. The extent of tumor blood vessel permeability is also controlled by the host microenvironment, and increases with the histological grade and malignant potential of tumors.7,8

Given the potency and toxicity of modern pharmacological agents, tissue selectivity is a major issue. In the delivery of chemotherapeutic agents to solid tumors this is particularly critical, since the therapeutic window for these agents is often small and the dose-response curve steep. Therefore, the idea of exploiting the well-documented vascular abnormalities of tumors, restricting penetration into normal tissue interstitium while allowing freer access to that of the tumor, becomes particularly attractive.

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