I have described herein the history, and controversial issues of the EPR (enhanced permeability and retention) effect, including various factors involved, heterogeneity, genetic mutational diversity, obstacles to the tumor blood flow or thrombi formation, and counter measures to overcome these problems in the EPR-based drug delivery. Also gaps between experimental models of mice, in contrast to practical human clinical setting are discussed. Issues of cell internalization, which is greatly affected by the nature of active pharmaceutical ingredient (API) was demonstrated using HPMA polymer(P)-conjugated-pirarubicin (THP) and P-doxorubicin, where there is more than 30 fold difference with P-THP being superior. Critical Importance of the enhancers of the EPR effect such as nitroglycerin is also described.

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I describe misunderstandings of the EPR effect in the former part of this review and criticism against the EPR effect in the latter part. The EPR effect was first presented in an article published in 1986, and has become a common concept not only in the Japan Society of DDS but also in other related societies in medical, engineering, and pharmaceutical fields. At present in these societies' meetings, the EPR effect may be cited without any explanation. In this situation, I think many misunderstandings may happen concerning the EPR effect. Additionally, discussion may be arisen what area the EPR effect covers. In the former part, I summarize historical backgrounds and a definition of the EPR effect, and then explain several points that may be misunderstood concerning the EPR effect. In the latter part, I cite one review paper that described criticism against the EPR effect, and express my opinion on this criticism. Although my opinion is opposite to this criticism in most points, I appreciate discussion raised by this criticism because criticism is essential in developments of science.

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A discovery of the EPR effect allowed for remarkable progress in a delivery of anti-cancer therapeutics using cancer-targeting nanoparticle. However, recent report on meta-analysis among several clinical trial with patients treated with liposomal doxorubicin revealed that liposomal doxorubicin was not superior to free doxorubicin in terms of therapeutic effect. This difference would be caused by the difference between non-clinical model and clinical model with regard to growth speed, tumor growth speed, tumor microenvironment, endpoint (tumor size vs. over survival). We would like to introduce this report in detail. In addition, to evaluate the effect of tumor microenvironment on the delivery of nanoparticle and to enhance that through remodeling tumor microenvironment, we have recently developed a new strategy that remodeling tumor microenvironment by siRNA delivery to tumor vasculature enhanced the intratumoral distribution of nanoparticles. Specifically in hyperangiogenic cancer, anti-angiogenic therapy by vascular endothelial growth factor receptor 2 (VEGFR2) enhanced the delivery of nanoparticles to tumor tissue, which was inconsistent with previous report. We herein would like to explain this contradiction in terms of tumor microenvironment and introduce our new strategy.

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Due to the long circulation time of polyethylene glycol (PEG)-modified liposomes (PEG liposomes) and the leakiness of the microvasculature in solid tumors, PEG liposomes containing anticancer drugs have been shown to accumulate preferentially in tumors. This phenomenon, known as the enhanced permeability and retention (EPR) effect, has been generally observed in many types of murine solid tumors and provides a good opportunity for passive targeting of liposomal anticancer drugs to tumor tissues. However, differences in the pathophysiological characteristics of tumors may result in different therapeutic effects in EPR effect-based therapy. In this review, various factors which would affect EPR effect-based therapy are summarized and are briefly introduced in a point-by-point fashion.

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Recently, the drug delivery with ultrasound and microbubbles has attracted much attention. This method can enhance the permeability of blood vessels due to induce oscillation and/or disruption of microbubbles inside the blood vessels under ultrasound exposure. In a clinical study, it was reported that the combination of ultrasound exposure with microbubbles and chemotherapy could be enhanced the anti-tumor effect. Therefore, it is expected that the modulation of microvascular permeability with ultrasound and microbubbles could be applied for the enhancement of EPR effect in cancer therapy with nano-sized drug carriers such as liposomes. Here, we will introduce the drug delivery with ultrasound and microbubbles and discuss the feasibility for the enhancement of EPR effect for nano-sized drug carriers.

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EPR effect is one of the most versatile and useful effect to deliver nano-medicine to solid tumor. However, the extravasation ability sometimes seems to be suppressed in some cases. Thus, enhancement of EPR effect will be useful to ensure and augment of therapeutic ability of nano-medicine. Here a liposome in which spontaneous niric oxide releaser was encapsulated is introduced as an enhancement system of EPR effect. The liposome releases nitric oxide with 35h of half-life time. When the liposome was injected from tail vein of CT26 tumor bearing mice, the liposome accumulation in the tumor increased twice comparing with empty liposome without any change of the liposome accumulation in other organs. Co-injection of the liposome and Doxil also enhanced the therapeutic effect of Doxil itself. The system will contribute cancer chemotherapy using nano-medicine.

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A unique phenomenon in solid tumors, enhanced permeability and retention（EPR） effect, is very famous for the development of macromolecular anticancer therapy. However, cancers with low vascular permeability posed a challenge for these EPR based therapeutic systems. An intrinsic vascular modulator such as nitric oxide（NO） could augment the intrinsic EPR effect. We have demonstrated that S―nitrosated human serum albumin dimer（SNO―HSA Dimer） becomes an enhancer of the EPR effect in various tumor-bearing mice models. Here, we summarized the enhanced effect of SNO―HSA Dimer on the anticancer effect of two types of macromolecular anticancer drugs, namely PEGylated liposomal doxorubicin（Doxil^®） and albumin bound paclitaxel nanoparticle（Abraxane^®）. In C26―bearing mice with highly permeable vasculature, SNO―HSA Dimer could increase tumor accumulation of these anticancer drugs and thereby their anticancer effects. Interestingly, the tumor accumulation of Doxil^® in B16―bearing mice, which are characterized by a low permeable vasculature, increased more 6―fold in the presence of SNO―HSA Dimer, and the improved accumulation of Doxil^® led to increased survival and decreased tumor volume. On the other hand, SNO―HSA Dimer also augmented the tumor growth inhibition of Abraxane^® in low vascular permeability B16―bearing mice. Furthermore, Abraxane^® combined with SNO―HSA Dimer showed higher antitumor activity and improved survival rate of SUIT2 human pancreatic cancer orthotopic model. We also showed that the administration of SNO―HSA Dimer had no effect on blood pressure, heart rate and biochemical parameters, suggesting that SNO―HSA Dimer alone is very safe. Accordingly, we conclude that SNO―HSA Dimer is promising for regulating the EPR effect and enhanced therapeutic effects of many macromolecular anticancer drugs.

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The EPR effect is principle concept of high molecular DDS and has been clearly verified worldwide in non-clinical experiments. However, it has not been widely used in clinics. Above all, therapy using DDS is not a mainstream technique in the field of oncology. To answer this discrepancy, we compared the clinical pancreatic cancer tissues with human pancreatic xenografts in nude mice and found a clear difference between the two. Specifically, the clinical pancreatic cancer tissues possessed abundant cancer stroma. Because tumor vessels are present in cancer stroma, it is reasonable to hypothesize that abundant stroma may be a barrier hindering the distribution of macromolecules, including DDS formulations, within cancer tissues. In contrast, pancreatic tumor xenografts contained only tumor cells and no stroma. From these results, we concluded that DDS is effective in experimental tumor xenografts because of the lack of tumor stroma, which may allow DDS to be distributed throughout the tumor. On the other hand, DDS is ineffective in clinical human pancreatic cancer because the tumor stromal barrier prevents DDS from reaching the cancer cells within the tissue. We now propose cancer stromal targeting (CAST) therapy in order to overcome the issue of stromal barrier in clinical cancers.

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It is known to be difficult for schizophrenia to maintain medication adherence, therefore the relapse and exacerbation of hospitalization risk due to lower adherence are regarded as unmet medical needs. To overcome this issue, ABILIFY MAINTENA^® （aripiprazole） for extended-release injectable suspension was developed using the property of lower solubility of aripiprazole hydrate crystals in neutral solution. In clinical trials, ABILIFY MAINTENA^® demonstrated that every 4 weeks injections maintained the effective plasma concentration and delayed the time to relapse of psychiatric symptoms significantly compared to the placebo group. Currently, ABILIFY MAINTENA^® is marketed in more than 30 countries including Japan, the United States and Europe, and it came to be used as one treatment option for schizophrenia. This article describes the characteristics of this drug formulation, the history of formulation development, pharmacokinetics, and clinical results.

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