Toward full understanding of the EPR effect in primary and metastatic tumor and issues of heterogeneity: For tumor selective delivery and imaging using nano-particles

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Hiroshi Maeda

Sojo University, Japan

: J Pharm Drug Deliv Res

Abstract

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Tumor selective targeting using macromolecular drugs was started when poly (styrene-co-maleic acid) was conjugated to protein (NCS) forming SMANCS in 1979. We then investigated most biocompatible plasma proteins, and synthetic polymers of various sizes for tumor uptake: We found >40 kDa polymers were selectively taken up into the tumor: This tumor selective uptake phenomenon was coined EPR (enhanced permeability and retention) effect of solid tumors in 1986: The EPR reflects architectural defect of tumor vasculature and excessive production of many vascular effectors as in inflammation, e.g., bradykinin, nitric oxide, etc. EPR effect was also demonstrated in metastatic cancers recently. Heterogeneity of EPR in many tumors may be caused by tumor thrombus or suppressed blood-flow. We showed several vascular mediators can augment EPR effect such as NO releasing agents and ACE-inhibitor (e.g., enalapril) which potentiates bradykinin. They not only restore vascular flow but also augment EPR effect for macromolecular delivery 2-3 folds. EPR effect will be similarly applied for delivery of fluorescent nanoprobes; it becomes beneficial for novel imaging and photodynamic therapy. Iv injection of fluorescent Zn-protoporphyrin nano probes in rat with autochthonous breast cancer, followed by 2-3 times photo-irradiation by endoscope, resulted in complete tumor regression. This advantage is also great value for in vivo tumor detection using fluorescent endoscope. The EPR effect is yetthe first step for selective tumor delivery. However, drug translocation to tumor cell-membrane and intracellular target are remaining issues. We will show our state-of-the-artfor these points, utilizing tissue-pH of tumor (acidic) and membrane transporter supregulated in tumors.

Biography

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Hiroshi Maeda is a world renowned expert in macromolecular therapeutics. He has created the world first polymeric-conjugate drug, SMANCS, approved for treatment of hepatoma in Japan. Consequently, he discovered the concept of EPR effect of macromolecular-drugs, ubiquitous mechanism for solid tumor selective targeting of polymeric drugs. He has received his MS from the University of California, Davis, Fulbright Student of PhD and MD at Tohoku University, Japan. He has published more than 450 papers in reputed journals. He was awarded Lifetime-Achievement-Award at Royal-Pharmaceutical-Society, Princess-Takamatsu-Award in Cancer Research, Tomizo-Yoshida-Award, highest award of Japan-Cancer-Association and also selected as most cited influential Scientist in Pharmacology by Thomson Reuters 2014 with an H-index of 89.

Email: hirmaeda@ph.sojo-u.ac.jp