Solid tumor has unique vascular architecture, excessive production of vascular mediators, and extravasation of macromolecules from blood vessels into the tumor tissue interstitium. These features comprise the phenomenon named the EPR effect of solid tumors, described in 1986. Our investigations on the EPR revealed that many mediators, such as bradykinin, NO, and prostaglandins, are involved in the EPR effect, which is now believed to be the most important element for cancer-selective drug delivery. However, tumors in vivo manifest great diversity, and some demonstrate a poor EPR effect, for example, because of impaired vascular flow involving thrombosis, with poor drug delivery and therapeutic failure. Another important element of this effect is that it operates in metastatic cancers. Because few drugs are currently effective against metastases, the EPR effect offers a great advantage in nanomedicine therapy. The EPR effect can also be augmented two to three times via nitroglycerin, ACE inhibitors, and angiotensin II-induced hypertension. The delivery of nanomedicines to tumors can thereby be enhanced. In traditional PDT, most PSs had low MW and little tumor-selective accumulation. Our hydroxypropylmetacrylamide-polymer-conjugated-PS, zinc protoporphyrin (apparent MW >50 kDa) showed tumor-selective accumulation, as revealed by fluorescent imaging of autochthonous cancers. After one i.v. injection of polymeric PS followed by two or three xenon light irradiation/treatments, most tumors regressed. Thus, nanoprobes with the EPR effect seem to have remarkable effects. Enhancing the EPR effect by using vascular modulators will aid innovations in PDT for greater tumor-targeted drug delivery.

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The enhanced permeability and retention (EPR) effect is a unique pathophysiological phenomenon of solid tumors that sees biocompatible macromolecules (>40 kDa) accumulate selectively in the tumor. Various factors have been implicated in this effect. Herein, we report that heme oxygenase-1 (HO-1; also known as heat shock protein 32) significantly increases vascular permeability and thus macromolecular drug accumulation in tumors. Intradermal injection of recombinant HO-1 in mice, followed by i.v. administration of a macromolecular Evans blue-albumin complex, resulted in dose-dependent extravasation of Evans blue-albumin at the HO-1 injection site. Almost no extravasation was detected when inactivated HO-1 or a carbon monoxide (CO) scavenger was injected instead. Because HO-1 generates CO, these data imply that CO plays a key role in vascular leakage. This is supported by results obtained after intratumoral administration of a CO-releasing agent (tricarbonyldichlororuthenium(II) dimer) in the same experimental setting, specifically dose-dependent increases in vascular permeability plus augmented tumor blood flow. In addition, induction of HO-1 in tumors by the water-soluble macromolecular HO-1 inducer pegylated hemin significantly increased tumor blood flow and Evans blue-albumin accumulation in tumors. These findings suggest that HO-1 and ⁄ or CO are important mediators of the EPR effect. Thus, anticancer chemotherapy using macromolecular drugs may be improved by combination with an HO-1 inducer, such as pegylated hemin, via an enhanced EPR effect. (Cancer Sci 2012; 103: 535-541) C onventional chemotherapy with small molecule drugs has been used for many types of cancer for decades. However, the therapeutic efficacy remains less than optimal, mostly because of a lack of tumor selectivity, which results in severe adverse side effects and prevents the use of high drug doses.(1)The development of tumor-targeted chemotherapy is critically important for more successful treatment.During investigations of targeting drugs to tumors, Matsumura and Maeda (2) found that macromolecular agents larger than 40 kDa selectively accumulate and remain in tumor tissues for long periods. This unique phenomenon in the blood vasculature of solid tumor tissues is quite different from that in normal tissues and was attributed to the unique anatomic and pathophysiologic characteristics of solid tumors. These features include: (i) extensive angiogenesis and hence high vascular density; (3,4) (ii) extensive extravasation (vascular permeability) induced by various vascular mediators, including bradykinin, (5-7) nitric oxide (NO), (7,8) vascular endothelial growth factor (VEGF), (9,10) prostaglandins produced via cyclo-oxygenases,and matrix metalloproteinases;(11) (iii) defective vascular architecture, such as the lack of a smooth muscle layer and large gaps between vascular endothelial cells; (12,13) and (iv) impaired lymphatic clearance from the tumor interstitial space. (14)(15)(16) The increased vascular permeability and defective vas...

Many diseases and pathological conditions, including ischemia/reperfusion (I/R) injury, are the consequence of the actions of reactive oxygen species (ROS). Controlling ROS generation or its level may thus hold promise as a standard therapeutic modality for ROS-related diseases. Here, we assessed heme oxygenase-1 (HO-1), which is a crucial antioxidative, antiapoptotic molecule against intracellular stresses, for its therapeutic potential via its inducer, hemin. To improve the solubility and in vivo pharmacokinetics of hemin for clinical applications, we developed a micellar hemin by conjugating it with poly(ethylene glycol) (PEG) (PEG-hemin). PEG-hemin showed higher solubility in water and significantly prolonged plasma half-life than free hemin, which resulted from its micellar nature with molecular mass of 126 kDa in aqueous media. In a rat I/R model, administration of PEG-hemin significantly elevated HO-1 expression and enzymatic activity. This induction of HO-1 led to significantly improved liver function, reduced apoptosis and thiobarbituric acid reactive substances of the liver, and decreased inflammatory cytokine production. PEGhemin administration also markedly improved hepatic blood flow. These results suggest that PEG-hemin exerted a significant cytoprotective effect against I/R injury in rat liver by inducing HO-1 and thus seems to be a potential therapeutic for ROS-related diseases, including I/R injury.

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