Barriers To Extravasation

As a consequence of temporal and spatial heterogeneity in tumor blood flow, solid tumors usually contain well-perfused, rapidly growing regions, and poorly perfused, often necrotic areas.1,3 As in normal tissues, diffusive and convective forces govern the movement of molecules into the inter-stitium of tumors. However, diffusion is believed to play a minor role in the movement of solutes across the endothelial barrier in comparison with bulk fluid flow. Examination of pressure gradients in experimental tumors has suggested that the movement of macromolecules and particulate materials out of the tumor blood vessels and into the extra-vascular compartment is remarkably limited. This has been attributed to a higher-than-expected interstitial pressure, in part due to a lack of functional lymphatic drainage, coupled with lower intra-vascular pressure.3 In addition, interstitial pressure tends to be higher at the center of solid tumors, diminishing towards the periphery, creating a mass flow movement of fluid away from the central region of the tumor.3 For example, the measured interstitial fluid pressure in invasive breast ductal carcinoma was 29 + 3 mm Hg, compared with 3.0 + 0.8 mm Hg in patients with benign tumors and — 3.0 + 0.1 mm Hg in patients with normal breast parenchyma.9 Nevertheless, the lower interstitial pressure in the periphery still permits adequate extravasation of fluid and macromolecules.

These pathophysiological characteristics have serious implications for the systemic delivery of not only low-molecular-weight and macromolecular agents, but also particulate delivery vehicles. Simply enhancing the plasma half-life of these agents (e.g., long-circulating carriers) will not necessarily lead to an increase in therapeutic effect.10 Furthermore, distribution, organization, and relative levels of collagen, decorin, and hyaluronan also impede the diffusion of extravasated macromolecules and particulate systems in tumors.11 Thus, diffusion of macromolecules and particles will vary with tumor types, anatomical locations, and possibly by factors that influence extracellular matrix composition and/or structure.

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