Bypassing the EPR effect with a nanomedicine harboring a sustained-release function allows better tumor control

Yao An Shen,1,* Ing Luen Shyu,2,* Maggie Lu,3 Chun Lin He,4 Yen Mei Hsu,2 Hsiang Fa Liang,3 Chih Peng Liu,3 Ren Shyan Liu,5,6 Biing Jiun Shen,7 Yau Huei Wei,1 Chi Mu Chuang2,4 1Institute of Biochemistry and Molecular Biology, School of Life Sciences, 2Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, 3Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, 4Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, 5Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, 6National PET/Cyclotron Center, Taipei Veterans General Hospital, Taipei, Taiwan; 7Division of Psychology, Nanyang Technological University, Singapore *These authors contributed equally to the work Abstract: The current enhanced permeability and retention (EPR)-based approved nanomedicines have had little impact in terms of prolongation of overall survival in patients with cancer. For example, the two Phase III trials comparing Doxil®, the first nanomedicine approved by the US Food and Drug Administration, with free doxorubicin did not find an actual translation of the EPR effect into a statistically significant increase in overall survival but did show less cardiotoxicity. In the current work, we used a two-factor factorial experimental design with intraperitoneal versus intravenous delivery and nanomedicine versus free drug as factors to test our hypothesis that regional (intraperitoneal) delivery of nanomedicine may better increase survival when compared with systemic delivery. In this study, we demonstrate that bypassing, rather than exploiting, the EPR effect via intraperitoneal delivery of nanomedicine harboring a sustained-release function demonstrates dual pharmacokinetic advantages, producing more efficient tumor control and suppressing the expression of stemness markers, epithelial-mesenchymal transition, angiogenesis signals, and multidrug resistance in the tumor microenvironment. Metastases to vital organs (eg, lung, liver, and lymphatic system) are also better controlled by intraperitoneal delivery of nanomedicine than by standard systemic delivery of the corresponding free drug. Moreover, the intraperitoneal delivery of nanomedicine has the potential to replace hyperthermic intraperitoneal chemotherapy because it shows equal efficacy and lower toxicity. In terms of efficacy, exploiting the EPR effect may not be the best approach for developing a nanomedicine. Because intraperitoneal chemotherapy is a type of regional chemotherapy, the pharmaceutical industry might consider the regional delivery of nanomedicine as a valid alternative pathway to develop their nanomedicine(s) with the goal of better tumor control in the future. Keywords: enhanced permeability and retention effect, liposome, paclitaxel, ovarian cancer&nbsp