Elsevier

Drug Discovery Today

Volume 11, Issues 17–18, September 2006, Pages 812-818
Drug Discovery Today

Review
Post Screen
Exploiting the enhanced permeability and retention effect for tumor targeting

https://doi.org/10.1016/j.drudis.2006.07.005Get rights and content

Of the tumor targeting strategies, the enhanced permeability and retention (EPR) effect of macromolecules is a key mechanism for solid tumor targeting, and considered a gold standard for novel drug design. In this review, we discuss various endogenous factors that can positively impact the EPR effect in tumor tissues. Further, we discuss ways to augment the EPR effect by use of exogenous agents, as well as practical methods available in the clinical setting. Some innovative examples developed by researchers to combat cancer by the EPR mechanism are also discussed.

Section snippets

The theory behind enhanced permeability and retention, pathophysiology and anatomy of tumor vasculature

When tumor cells multiply, cluster together and reach a size of 2–3 mm angiogenesis is induced, to cater for the ever-increasing nutrition and oxygen demands of the growing tumor [3]. This neovasculature differs greatly from that of normal tissues in microscopic anatomical architecture [4]. For instance, the blood vessels in the tumor are irregular in shape, dilated, leaky or defective, and the endothelial cells are poorly aligned or disorganized with large fenestrations. Also, the perivascular

Vascular endothelial growth factor

Vascular permeability factor (VPF) [15], identical to vascular endothelial growth factor (VEGF), has a significant role in tumor angiogenesis 16, 17. In addition to being a mitogen for endothelial cells, it plays a pivotal role in tumor growth and, perhaps, in metastasis because of its induction of vascular permeability [15]. Increased vascular permeability will lead to an enhanced extravasation of macromolecules. Besides VEGF, the EPR effect is further amplified by numerous other vascular

Angiotensin-II-induced hypertension

The vascular density of many, if not all, tumors is higher than that of normal tissues. Further, tumor blood vessels lack a smooth-muscle layer, which plays a vital role in regulating blood pressure and flow. In normal blood vessels, the smooth-muscle layer responds to vascular mediators such as BK, acetylcholine, NO and calcium via receptors on vascular smooth-muscle cells, helping to maintain constant blood flow volume. In normal tissues, when hypertension is induced by infusing

Prolonging half-life, stealth-character and reduced antigenicity

Because accumulation of macromolecules by the EPR effect is a progressive phenomenon, it is essential that the drugs are stable in plasma for long time periods. In addition to prolonging the half-life in plasma of low-molecular-weight drugs or proteins, polymer conjugation also guides the drugs to their target by the EPR effect [51]. It also confers stealth character and suppresses antigenicity of the proteinaceous drugs, as well as diminishing uptake by the reticuloendothelial system (RES) or

The SMANCS–polymer conjugate of copoly(styrene maleic-acid) with neocarzinostatin

The first prototype macromolecular anticancer agent, SMANCS, developed in our group, was approved for clinical use in Japan in 1993. The plasma half-life of SMANCS is ∼20 times longer than that of native NCS 2, 14, 38, 46. Further, NCS increased lipid solubility after conjugation with SMA, which enabled administration of SMANCS together with the lipid contrast agent Lipiodol®. SMANCS–Lipiodol® (injected via the tumor-feeding artery) resulted in drug retention >2000-fold higher in tumor tissue

Conclusion

The EPR effect is commonly observed in most solid tumors, either primary or metastatic in nature. The EPR effect is modulated or mediated by various factors produced by tumor cells, infiltrating leukocytes or even tumor-surrounding normal cells.

Obviously, many vascular mediators, such as BK, PGs and NO, also affect normal blood vessels near tumor tissue. Also, vascular density and microanatomical defects play important roles in this phenomenon. The EPR effect will confer most macromolecular and

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