Mechanism of tumor-targeted delivery of macromolecular drugs, including the EPR effect in solid tumor and clinical overview of the prototype polymeric drug SMANCS☆
Introduction
Tumor vessels have recently been receiving more attention than ever; the major focus of interest being tumor angiogenesis and its inhibition. Among the various endothelial growth factors, a particular focal point is vascular endothelial growth factor (VEGF), which was identified as vascular permeability factor (VPF) by Senger et al. [1]. VPF facilitates the extravasation of blood plasma components into the interstitial space of tumor tissues through the blood vessel walls, which results in nutritional support and oxygen supply for the rapidly growing tumor cells. We have also found many other potent vascular permeability mediators in tumor tissues, such as bradykinin, nitric oxide, peroxynitrite, collagenase (matrix metalloproteinases, MMPs) and prostaglandins [2], [3], [4], [5], [6], [7].
The accumulation and retention of polymeric drugs are greatly enhanced in tumor tissue compared with those in normal tissue, a phenomenon now known as the EPR (enhanced permeability and retention) effect of macromolecules and lipidic particles in solid tumor [8], [9], [10], [11], [12]. This effect is applicable only to macromolecules and lipidic particles, not to low-molecular-weight compounds; the category to which most drugs in use today belong [3], [4], [5], [7], [8], [9], [10]. Low-molecular-weight compounds such as mitomycin C are distributed freely by diffusion to various tissues and organs; the compounds move against the concentration gradient until finally an equilibrium results. Their concentration in tumor cannot be higher than that in blood plasma, nor can they be retained at high concentrations in tumor for a significant time period because of rapid excretion (washout) into the blood stream. The plasma concentration also diminishes rapidly as a result of efficient renal clearance via the urine. In contrast, macromolecules and polymeric drugs are retained in tumor tissue at a much higher concentration than that in plasma [7], [8], [9], [10], [11], [12], [13]. An example of tumoritropic accumulation of a polymeric drug is shown in Fig. 1. There is thus a great difference between low- and high-molecular-weight compounds in their intratumor accumulation. This phenomenon, the EPR effect, is now recognized as a general characteristic of viable and rapidly growing solid tumor. Another general characteristic is the architectural defectiveness of tumor blood vessels, which also causes enhanced leakiness. The various factors affecting the EPR effect are summarized in Table 1.
The EPR effect is also observed around the periphery of the tumor, i.e., in normal tissues surrounding the tumor, because of the variety of vascular mediators found there. Polymeric drugs may be cleared more rapidly from normal tissue than from tumor tissue via lymphatic drainage, however. All of these data indicate that tumor vasculature can be an ideal target for tumor-selective delivery of macromolecular anticancer agents [7], [8], [9], [10], [11], [12], [13], [14], [15].
Section snippets
Water-soluble polymer-conjugated drugs
In this section we touch only briefly on water-soluble injectable drugs and to targeting cancer. At least two such anticancer drugs developed long time ago, are used clinically. SMANCS, or SMA [polystyrene-co-maleic acid-half-butylate] copolymer conjugated with neocarzinostatin (Fig. 2), was the first in this category to be developed, in 1979 [16], [17]. SMANCS, which has a mass of 16 kDa, with albumin-binding and lipophilic characteristics, has been used experimentally in many patients with
Clinical effects of SMANCS
In many previous reports we have described the effect of SMANCS on primary hepatoma (hepatocellular carcinoma) [33], [34], [35], [36]; we used SMANCS formulated with the lipid contrast medium Lipiodol (SMANCS/Lpd) [33], [34]. Arterially administered SMANCS/Lpd can be targeted to cancer tissue with great efficiency, i.e., the tumor/blood plasma ratio is greater than 2000 [37]. The, EPR effect is clearly operative for tumor-selective targeting using Lipiodol as well as the first-pass effect. In
Acknowledgements
We would like to thank Drs. Y. Matsumura, K. Hori, J. Wu, T. Akaike and many other colleagues for this work, and Ms. Judith B. Gandy for editing the English version of the manuscript and Ms. Setsuko Yatomi for typing. Grants in Aid for Cancer Research from the Ministry of Education Science and Culture, and the Ministry of Health and Welfare, Japan, are highly acknowledged.
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- ☆
This article is dedicated to the memory of our long-time colleague Shojiro Maki, M.D., who died on 9 March, 1999. Dr. Maki devoted himself to the clinical development of SMANCS, and we shared with him his great joy in curing numerous cancer patients all over the world. He was a resident of Kikuchi City, Kumamoto, Japan, and is survived by his wife Kazumi and three daughters, Kanako, Sakiko and Yoko. All daughters will engage in the medical profession.