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regarded as a gold standard in drug design for new anti-cancer agents ' ' . This article will, therefore, describe the mechanism of vascular permeability effect in tumor tissues, macromolecular drug delivery, and pathophysiology of tumor vessels using SMANCS as the prototype, and also a few other new polymeric anticancer agents will be discussed briefly.

2. MECHANISM OF ENHANCED VASCULAR PERMEABILITY AND RETENTION (EPR) EFFECT OF SOLID TUMOR TISSUE

Blood vessels in most solid tumors possess unique characteristics that are not usually observed in normal blood vessels. Examples of such characteristics are summarized in Table 1:

(i) extensive angiogenesis and hence high vascular density 9 10;

(ii) extensive extravasation (vascular permeability) induced by various vascular mediators such as (a) bradykinin, which is produced via the activated kallikrein-kinin cascade involving various proteolytic steps 3-5, 11-14, (b) nitric oxide (NO) generated by the inducible form of nitric oxide synthase (iNOS) in leukocytes or in tumor cells 14-16,

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(c) VPF/VEGF and other cytokines , , (d) prostaglandins involving cyclooxygenases 14 21 and our unpublished data, and (e) matrix metalloproteinases (MMPs/collagenases)22;

(iii) defective vascular architecture 23-25;

(iv) impaired lymphatic clearance from the interstitial space of tumor tissues 3 4 26-30 .

Table !. Factors affecting the EPR effect of macromolecular drugs in solid tumor

1. Active angiogenesis and high vascular density

2. Extensive production of vascular mediators that facilitate extravasation a) bradykinin, b) nitric oxide, c) VPFVEGF, d) prostaglandins, e) collagenase (matrix metal loproteinases, MMPs), f) peroxyni trite, etc.

3. Defective vascular architecture: for example, lack of smooth muscle layer cells, tack of or reduced receptors for angiotensin II, large gap in endothelial cell-cell junctions, anomalous conformation of tumor vasculature (branching or stretching etc.)

4. Impaired lymphatic clearance of macromolecuies and lipids from interstitial tissue (-┬╗retention)

The characteristics of vascular pathophysiology just enumerated, i.e., enhanced extravasation of macromolecular compounds through blood vessels in tumor tissues and the impaired clearance of the macromolecules and lipidic particles from the interstitial space of tumor tissue contributes to the prolonged retention of these drugs in tumor 3 4 27-30 In normal tissues, however, the lipid contrast medium Lipiodol and lipids as well as plasma proteins and macromolecules are cleared from the reticuloendothelial/ lymphatic system 7 26-30. To describe this phenomenon related to the fate of macromolecular drugs and lipids in solid tumor, we coined the term EPR

(enhanced permeability and retention) effect in 1984 3 26 31. According to the EPR concept, biocompatible macromolecules accumulate at much higher (> 6 fold more) concentrations in tumor tissues than in normal tissues

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or organs, even higher than those in plasma26, 27, 30, 31. This EPR effect can be observed with macromolecules having an apparent molecular size larger than 50 kDa (Figure 1) which have long plasma half-lives 3 4 26, 31. It is also seen with large liposomes and some lipids (edible oils) in various experimental as well as human tumor systems 25-30, such as sarcoma 180, colon 38 adenocarcinama, Walker 256 carcinoma, melanoma B16, AH (Yoshida hepatoma) 109B and 136B, VX-2, in mice, rats, and rabbits respectively; and most of human solid tumors, as described later. It should be noted that non-stealth liposome are, however, cleared from circulation or before delivery to the target by macrophages via phagocytosis as shown in earlier studies in 1970s. Therefore, in general, most stealth biocompatible polymeric drugs accumulate in tumor tissue at concentrations 5-10 times higher than the concentration in plasma 24 hr after intravenous injection, and frequently at levels more than 10 times higher than that in normal tissue such

O A ^/f Ol as noncancerous muscle ' ' . The concept of EPR effect in tumor tissue is depicted in Figure 1.

A Normal tissue

B Tumor tissue

Figure I. Schematic representation of differences in vascular anatomy of normal tissue (A) and tumor tissue (B). Note the excessive network development of vessels and extravasation of macromolecules and lipid particles in tumor (B). (A from Courtice (7), and B from Maeda

Figure I. Schematic representation of differences in vascular anatomy of normal tissue (A) and tumor tissue (B). Note the excessive network development of vessels and extravasation of macromolecules and lipid particles in tumor (B). (A from Courtice (7), and B from Maeda

Most conventional low molecular weight drugs have a plasma half-life of less than 3 min in mouse. However, it takes about 6 hr or longer for drugs in circulation to exert the EPR effect (Figure 2A). This means that any candidate drug must have a large molecular size, above the renal clearance threshold to circulate for a long time. Indeed, as shown in Figure 2B, the plasma AUC (area under the concentration curve) paralleled the accumulation of drug in tumor. Polymer conjugation confers increased residence time of drugs in plasma to a great extent, when compared with the native low molecular drugs. For example, we found that the ti/2 of neocarzinostain (12 kDa) in mice is 1.8 min, whereas, the ti/2 for its conjugate with poly(styrene-co-maleic acid)half-n-butyl ester copolymer (SMA), known as SMANCS becomes about 19 min, i.e., a 10-fold increase.

Native superoxide dismutase (SOD, 30 kDa) had a ti/2 of about 3 min in mice, whereas SMA and other polymer conjugates has a tj/2 of 25 min or longer. The ti/2 of native human interferon-a (approx. 20 kDa) in human plasma was about 8 hr when given intramuscularly, which became 80 hr after PEG conjugation. These data are summarized in Tables 2 and 3.

Table 2. Plasma clearance times of various proteins and their polymer conjugates or modified proteins (from Ref. 4 with permission)_

Protein Type of polymer Molecular 11/2 t i/[o Test or modification mass (kDa)_animal

Table 2. Plasma clearance times of various proteins and their polymer conjugates or modified proteins (from Ref. 4 with permission)_

Protein Type of polymer Molecular 11/2 t i/[o Test or modification mass (kDa)_animal

Neocarzinostatin (NCS)

None

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