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

Yao An Shen; Ing Luen Shyu; Maggie Lu; Chun Lin He; Yen Mei Hsu; Hsiang Fa Liang; Chih Peng Liu; Ren Shyan Liu; Biing Jiun Shen; Yau Huei Wei; Chi Mu Chuang

doi:10.2147/IJN.S78321

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

Int J Nanomedicine. 2015 Mar 30:10:2485-502. doi: 10.2147/IJN.S78321. eCollection 2015.

Authors

Affiliations

¹ Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan.
² Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
³ Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan.
⁴ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan.
⁵ Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan ; National PET/Cyclotron Center, Taipei Veterans General Hospital, Taipei, Taiwan.
⁶ Division of Psychology, Nanyang Technological University, Singapore.
⁷ Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan ; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan.

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; ovarian cancer; paclitaxel.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents*
Delayed-Action Preparations*
Humans
Nanomedicine*
Neoplasms* / drug therapy
Neoplasms* / pathology
Research Design*

Substances

Antineoplastic Agents
Delayed-Action Preparations