The enhanced permeability and retention (EPR) effect in tumor vasculature: the key role of tumor-selective macromolecular drug targeting

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Introduction

Increasing attention has been paid in recent years to tumor angiogenesis and its control, with a focus on vascular endothelial growth factor (VEGF). Inhibition of angiogenesis by various antidotes or inhibitors such as endostatin and angiostatin is the most exciting issue in tumor biology, and for patients longing for a cure for cancer.

Tumor vascular permeability factor (VPF) was initially identified by Senger et al. in the laboratory of Dvorak (1) and was later confirmed as identical to VEGF 2., 3., 4., 5.. Although more attention has been focused on angiogenesis, the other side of biological activity of VEGF, the enhancement of vascular permeability also plays a critically important role in tumor growth to facilitate an adequate supply of nutrients and possibly oxygen to meet the great demands of rapidly growing tumors. Embolization with or without anticancer agents results in tumor regression or necrosis, although it is not fully effective in eradicating tumor cells because tumors quickly regenerate lateral neovasculature and nullify the embolization effect. Antibody directed against VEGF also had a limited effect in controlling the tumor growth in rodent models unable to eradicate the tumor (6), although clinical application of this method still must be explored.

Tumor vascular permeability is important not only in tumor biology but also in delivery of macromolecular anti-cancer agents (see Refs. 7., 8., 9., 10. for review). Here, the issue of vascular permeability is concerned with macromolecular (or polymeric) drugs with which highly selective targeting of drugs for tumors becomes possible. Such selective targeting is not possible with low-molecular-weight substances, as described later in this article. Small molecules, as are many of the drugs being used today for chemotherapy, do not discriminate tumor tissue from normal tissue; they reach most normal tissues and organs as well as tumor tissues by free diffusion-dependent equilibrium. For example, common drugs such as antibiotics spread throughout the body within a few minutes after subcutaneous injection. Like inflammatory tissues, tumor tissues exhibit extravasation of macromolecules, including plasma proteins and liposomes. However, unlike the situation with tumor tissues, clearance of macromolecules and lipids from the interstitial space of normal and inflammatory tissues proceeds rapidly and steadily via the lymphatic system, even in the inflammatory state after extravasation from blood vessels. Clearance of macromolecules and lipids from tumor is so impaired that they remain in the tumor interstitium for a long time 7., 8., 9., 10., 11.. This phenomenon has been characterized and termed the tumor-selective enhanced permeability and retention (EPR) effect of macromolecules and lipidic particles. The EPR concept is now regarded as a “gold standard” in the design of new anti-cancer agents 7., 8., 12.. This article will therefore describe the vascular permeability effect in tumor tissues, macromolecular drug delivery, and pathophysiology of tumor vessels.

Section snippets

Vascular permeability of solid tumor tissue: enhanced permeability and retention effect of macromolecules and lipids

After the “magic bullet” concept was proposed by Paul Ehrlich at the turn of the 20th century, many attempts have been made, to discover nontoxic cancer therapeutic agents. It was realized in a sense during the 1940s that penicillin and other antibiotics had selective toxicity for bacteria and not for the host, and in the 1970s, many reports were published on the so-called tumor-associated antigens. Thus, the missile drugs concept, in which an antibody, particularly a monoclonal antibody, is

Modulation of tumor blood flow and augmentation of the EPR effect

In 1981, Suzuki et al. found that elevating systemic blood pressure by infusing angiotensin II in tumor-bearing rats resulted in an increase of tumor blood flow by 2–6 times, in parallel to the blood pressure applied, whereas the blood flow in normal organs and tissues remained constant. In other words, vessels in normal organs, but not in cancerous tissue, show excellent homeostatic autoregulation of blood flow (Fig. 3) (43).

My colleagues and I investigated whether this increased tumor blood

Tumor-selective drug targeting by arterial injection of a lipid formulation and with tumor-imaging capability

My colleagues and I have developed the macromolecular anticancer agent SMANCS 7., 8., 31., 32., 49., 50. as an active principle with Lipiodol as a carrier, given by arterial injection (catheter) via the tumor-feeding arteries 49., 50., 51., 52., 53., 54., 55., 56.. Lipiodol is an iodinated ethyl ester of poppyseed oil manufactured by Laboratoire Guerbet in France; it can be administered intraarterially upstream from the tumor-feeding artery, i.e., the hepatic artery for hepatoma, and the

Summary

Enhanced vascular permeability of tumor and angiogenesis both sustain tumor growth mediated by many vascular mediators and high vascular density. Impaired reticuloendothelial/lymphatic clearance of macromolecules from the tumor, or lack of such clearance, is another unique characteristic of tumor tissue (Fig. 9). The enhanced permeability and retention (EPR) effect is the basis for the selective targeting of macromolecular drugs to tumor, and the EPR concept is now utilized for selective

Acknowledgements

I would like to thank my former and present colleagues and friends for their collaboration in conducting the experiments described here, including Drs. T. Konno, Y. Matsumura, S. Maki, T. Sawa, J. Takeshita, J. Wu, and T. Akaike, to name a few. Thanks are also due to Ms. Judith B. Gandy for high-quality editing of the English version of the manuscript. Work was supported by the Japanese Ministry of Education, Science and Culture as Grant in Aid for Science Research in Cancer and General Section.

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References (59)

  • T Konno

    Targeting chemotherapy for hepatomaarterial administration of anticancer drugs dissolved in Lipiodol

    Eur. J. Cancer

    (1992)
  • H Maeda et al.

    Tumor vascular permeability and the EPR effect in macromolecular therapeuticsa review

    J. Control. Release

    (2000)
  • D.R Senger et al.

    Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid

    Science

    (1983)
  • R.A Rosenthal et al.

    Conditioned medium from mouse sarcoma 180 cells contains vascular endothelial growth factor

    Growth Fact.

    (1990)
  • D.W Leung et al.

    Vascular endothelial growth factor is a secreted angiogenic mitogen

    Science

    (1989)
  • P.J Keck et al.

    Vascular permeability factor, an endothelial cell mitogen related to PDGF

    Science

    (1989)
  • M Asano et al.

    Inhibition of tumor growth and metastasis by an immunoneutralizing monoclonal antibody to human vascular endothelial growth factor/vascular permeability factor

    Cancer Res.

    (1995)
  • H Maeda et al.

    Tumoritropic and lymphotropic principles of macromolecular drugs

    Crit. Rev. Ther. Drug Carrier Sys.

    (1989)
  • H. MAEDA, Polymer conjugated macromolecular drugs for tumor-specific targeting, pp. 95–116 in Polymer Site Specific...
  • H Maeda et al.

    Conjugation of anticancer agents and polymersadvantages of macromolecular therapeutics in vivo

    Bioconjugate Chem.

    (1992)
  • F. C. COURTICE, The origin of lipoprotein, pp. 89–126 in Lymph and Lymphatic System (H. S. MEYERSEN, Chairman) Charles...
  • F.M Muggia

    Doxorubicin–polymer conjugatesfurther demonstration of the concept of enhanced permeability and retention

    Clin. Cancer Res.

    (1999)
  • J Folkman

    Tumor angiogenesistherapeutic implications

    N. Engl. J. Med.

    (1971)
  • Y Matsumura et al.

    Involvement of the kinin-generating cascade in enhanced vascular permeability in tumor tissue

    Jpn. J. Cancer Res.

    (1988)
  • Y Matsumura et al.

    Kinin-generating cascade in advanced cancer patients and in vitro study

    Jpn. J. Cancer Res.

    (1991)
  • J Wu et al.

    Modulation of enhanced vascular permeability in tumors by bradykinin antagonist, a cyclooxygenase inhibitor, and a nitric oxide scavenger

    Cancer Res.

    (1998)
  • H Maeda et al.

    Enhanced vascular permeability in solid tumor is mediated by nitric oxide and inhibited by both nitric oxide scavenger and nitric oxide synthase inhibitor

    Jpn. J. Cancer Res.

    (1994)
  • K Doi et al.

    Excessive production of nitric oxide in rat solid tumor and its implication in rapid tumor growth

    Cancer

    (1996)
  • H.R Reichman et al.

    Effect of steroids and nonsteroid anti-inflammatory agents on vascular permeability in a rat glioma model

    J. Neurosurg.

    (1986)
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