Hiroshi Maeda
Sojo University, Japan
Title: 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
Biography
Biography: Hiroshi Maeda
Abstract
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 >40KDa-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, eg. 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 (eg. 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 nanoprobes 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. rnThe EPR effect is yet the 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-art-for these points, utilizing tissue-pH of tumor (acidic), and membrane transporters upregulated in tumors.