Drug Designing: Open Access
Open Access

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

International Conference and Expo on Drug Discovery & Designing

August 11-13, 2015 Frankfurt, Germany

Hiroshi Maeda, Jun Fang, Kenji Tsukigawa and Hideaki Nakamura

Posters-Accepted Abstracts: Drug Des

Abstract :

Tumor 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.
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-art-for these points, utilizing tissue-pH of tumor (acidic), and
membrane transportersupregulated in tumors.