Tumor tissue permeability

In cancer treatment, passive targeting of macromolecular carriers to tumors is a commonly used approach. This passive targeting is based on the enhanced permeability and retention (EPR) effect, which leads to an accumulation of the high molecular weight carrier in the tumor tissue. The EPR effect arises from the different physiology of tumor vasculature, where the vessel walls are highly porous and lack the tight junctions that are present in healthy tissue. As a result, macromolecular carriers extravasate and accumulate preferentially in tumor tissue relative to normal tissues [63, 64]. 

A further consideration is that under pathological conditions, endothelium exhibits modified characteristics. In general, the permeability is enhanced this phenomenon is called the enhanced permeability and retention (EPR) effect. For example, the endothelial fenestrations in inflammation sites can be as large as 0.2 pm. Also, in tumor tissue, even larger fenestrations can be found. However, in this case, the pattern is not uniform and depends on the tumor type and stage of development. Even within one... 

As a predictor of the concentration of cisplatin in normal peritoneal tissues, these data indicate a steady-state penetration depth (distance to half the surface layer concentration) of about 0.1 mm (100 tm). If this distance applied to tumor tissue, penetration even to three or four times this depth would make it difficult to effectively dose tumor nodules of 1- to 2-mm diameter. Fortunately, crude data are available from proton-induced X-ray emission studies of cisplatin transport into intraperitoneal rat tumors, indicating that the penetration into tumor is deeper and is in the range of 1-1.5 mm (10). Such distances are obtained from Equation 9.5 or 9.5 only if k is much smaller than in normal peritoneal tissues — that is, theory suggests that low permeability coefficient-surface area products in tumor (e.g., due to a developing microvasculature and a lower capillary density) may be responsible for the deeper tumor penetration. 

A number of studies have examined the use of a dendrimer drug carrier to treat a variety of tumors. One approach has been based on the exploitation of the enhanced permeability and retention effect (EPR effect) to localize drug conjugates in tumor tissue. " A second approach has involved the conjugation of a... 

Matsumra Y, Kimura M, Yamamoto T, et al. Involvement of the kinin-generating cascade in enhanced vascular permeability in tumor tissue. Jpn J Cancer Res 1988 79 1327-1334. 

Experimentally Determined Tumor Normal Tissue Permeability Ratios3... 

Tumor Normal tissue Solute radius (nm) Tumor normal permeability Ref. 

Fig. 1. Microcirculation of a human colon carcinoma grown in the dorsal skin chamber in a severe-combined immunodeficient mouse. (Adapted from Leunig et al., 1992b.) Note that angiogenesis leads to formation of numerous blood vessels. Such a transparent preparation can permit noninvasive, continuous measurement of transport processes in normal and tumor tissues (Jain, 1985b). Parameters we can measure include hemodynamic (e.g., blood flow, vasomotion) metabolic (e.g., pH, p02, Ca2+) transport (e.g., permeability, diffusion, binding), and cell-cell interactions (e.g., adhesion, deformability).

The passive targeting of polymeric micelles to solid tumors can be achieved by the enhanced permeability and retention effect (EPR effect). Maeda and his coworkers presented this new drug targeting strategy in 1986 (31,32). As illustrated in Fig. 3, the vascular permeability of tumor tissues is enhanced by the actions of secreted factors such as kinin. As a result of this increased vascular permeability, macromolecules selectively increase their transport from blood vessels to tumor tissues. Furthermore, the lymphatic drainage system does not operate effectively in tumor tissues. 

We demonstrated that BK is an important mediator of EPR effect in cancer [36]. Figure 5 shows network of BK and other mediators involving in EPR effect. BK interacts with various proinflammatory factors involving vascular permeability. For instance, it is also known to activate endothelial cell-type nitric oxide synthase (eNOS), which is one of the primary enzymes to produce NO from L-arginine. We have reported that the BK-generating cascade is activated in tumor tissues [36]. More importantly, malignant ascetic and pleural fluids would be caused by activation of kallikrein-kinin system in carcinomatosis [37]. 

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