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

T selective targeting using macromolecular drugs was started when poly (styrene-co-maleic acid) was conjugatedto protein (NCS) forming SMANCS in 1979.We then investigated most biocompatible plasma proteins,andsynthetic polymers of various sizesfor tumor uptake:We found >40KDa-polymers were selectively taken up into the tumor: This tumor selective uptakephenomenonwas coined EPR (enhanced permeability and retention)effect of solid tumors in 1986: The EPR reflectsarchitectural defect of tumor vasculature and excessive production of many vascular effectors as in inflammation, eg. bradykinin, nitric oxide, etc. EPR effect was also demonstratedin metastatic cancersrecently. 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 potentiatesbradykinin.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 novelimaging and photodynamic therapy. Iv injection of fluorescent Zn-protoporphyrinnanoprobes in rat withautochthonous breast cancer, followed by 2-3 times photo-irradiation by endoscope, resultedin complete tumor regression. This advantage is also great value for in vivo tumor detection using fluorescent endoscope.