Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review
Introduction
In tumor biology, little is known about tumor-selective or tumor-specific characteristics compared with those of normal tissues or organs. The concept of the enhanced permeability and retention (EPR) effect in solid tumors is one of the few tumor-specific characteristics that is becoming a gold standard in antitumor drug delivery [1], [2], [3], [4], [5], [6]. The EPR effect is predominantly observed for biocompatible macromolecules (or macromolecular drugs and lipids) [1], [2], [3], [4], [5], [6], [7], [8]. Furthermore, even targeting of minute particles such as liposomes to the tumor appears to be based on this mechanism.
We previously reported that most solid tumors have elevated levels of vascular permeability factors such as bradykinin, nitric oxide (NO) [9], [10], [11], [12], [13], and, more recently, peroxynitrite (ONOO−) [14]. Proteinaceous vascular permeability factor (VPF) [15], which is identical to vascular endothelial growth factor (VEGF) [16], is also known to be produced actively in tumor tissue; its effect is most likely mediated indirectly by extensive production of NO [11], [12], [13], [17]. Enhanced vascular permeability is also observed in granuloma and inflammatory and infected tissues [18], [19], [20], [21], with resultant extravasation of plasma proteins as well as macromolecules and lipid particles into the interstitial space. Table 1 summarizes various factors involved in vascular permeability.
Section snippets
Vascular permeability and lymphotropic clearance
During the distribution study of the macromolecular anticancer agent SMANCS and various plasma proteins and other highly water-soluble small acidic proteins, e.g. neocarzinostatin (12 kDa) and chicken ovomucoid (29 kDa), we found considerable time-dependent accumulation of SMANCS and plasma proteins larger than 60 kDa [1], [2], [4], [6], [22], [23], [24], [25] (Fig. 1, Fig. 2). Furthermore, when macromolecules, including SMANCS and neocarzinostatin, were injected subcutaneously, we found
Concept of the enhanced permeability and retention (EPR) effect of macromolecules in solid tumors
Our previous data using biocompatible plasma proteins and synthetic polymers or their various conjugates showed that these macromolecules are entrapped or accumulate in solid tumors and that they are retained there at high concentrations for prolonged periods (more than 100 h) [e.g. [1], [2], [4], [6], [7], [8], [22], [23], [24], [28], [30]]. This phenomenon led to coining of the term enhanced permeability and retention (EPR) effect of macromolecules and lipids in solid tumors. More recently,
Factors involved in the EPR effect in solid tumors and its enhancement or modulation
We initially found, as described in Section 1, selective accumulation of plasma albumin (a macromolecule) at the site of bacterial infection with inflammation, where extracellular proteases produced by bacteria are capable of triggering the bradykinin cascade [18], [19], [21], [37], [38] (Fig. 5).
We suspected that bradykinin is also responsible for ascitic fluid accumulation as a result of extravasation caused by similar factors in rodent and human tumors. Indeed, we identified the presence of
Unique blood flow in tumor: tumor-specific vascular pathophysiology
In 1981, Suzuki et al. reported that blood flow in tumor tissue was quite different from that in all other normal tissues, in response to hypertension induced by infusing angiotensin II [50]. Fig. 9 shows this result: tumor blood flow was selectively increased in response to angiotensin II-induced hypertension when systemic arterial blood pressure was elevated by intravenous administration of this agent. Blood flow in normal organs such as kidney, bone marrow, brain and liver remained constant
Modulation of vascular permeability by inhibitors of vascular mediators or antagonists
By the use of ACEIs such as enalapril or temocapril, which also inhibit the degradation of bradykinin as described above, one can ultimately activate endothelial NOS because the level of bradykinin is increased. Thus, the EPR effect becomes more apparent, and such inhibitors enhance delivery of macromolecular drugs or components to the tumor.
In addition, elevation of blood pressure by infusing angiotensin II is another way to enhance drug delivery to the tumor by two to three times while
Conclusion
More efficient drug delivery to the tumor, especially of macromolecular drugs, may be possible by enhancing the EPR effect using vascular permeability mediators or potentiators. Suppression of the EPR effect by the use of appropriate inhibitors or antidotes, such as bradykinin antagonist HOE 140 and protease inhibitors or inducible NOS inhibitors, may become possible. Thus, one may be able to suppress tumor growth and tumor metastasis and to improve the clinical course of cancer patients.
Acknowledgements
We would like to thank Ms. Judy Gandy for English editing and Dr. T. Akaike of the Department of Microbiology, Kumamoto University School of Medicine for his discussion, and Ms. Rie Yoshimoto and Ms. Fumi Ikeda for typing and secretarial work. This work was supported by a Grant-in-Aid (06282247) for Research on Cancer (to H.M.) from the Ministry of Education, Science, Sports and Culture (Monbusho) of Japan, and the Sagawa Foundation for Frontier Science and Technology (to H.M., 1998).
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