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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2485-502
Number of pages18
JournalInternational Journal of Nanomedicine
Volume10
DOIs
Publication statusPublished - 2015
Externally publishedYes

Fingerprint

Nanomedicine
Medical nanotechnology
Tumors
Permeability
Neoplasms
Chemotherapy
Drug Therapy
Survival
Pharmaceutical Preparations
Lymphatic System
Pharmacokinetics
Epithelial-Mesenchymal Transition
Tumor Microenvironment
Drug Industry
Multiple Drug Resistance
United States Food and Drug Administration
Liver
Design of experiments
Doxorubicin
Drug products

Keywords

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

Cite this

Bypassing the EPR effect with a nanomedicine harboring a sustained-release function allows better tumor control. / Shen, Yao An; Shyu, Ing Luen; Lu, Maggie; He, Chun Lin; Hsu, Yen Mei; Liang, Hsiang Fa; Liu, Chih Peng; Liu, Ren Shyan; Shen, Biing Jiun; Wei, Yau Huei; Chuang, Chi Mu.

In: International Journal of Nanomedicine, Vol. 10, 2015, p. 2485-502.

Research output: Contribution to journalArticle

Shen, YA, Shyu, IL, Lu, M, He, CL, Hsu, YM, Liang, HF, Liu, CP, Liu, RS, Shen, BJ, Wei, YH & Chuang, CM 2015, 'Bypassing the EPR effect with a nanomedicine harboring a sustained-release function allows better tumor control', International Journal of Nanomedicine, vol. 10, pp. 2485-502. https://doi.org/10.2147/IJN.S78321
Shen, Yao An ; Shyu, Ing Luen ; Lu, Maggie ; He, Chun Lin ; Hsu, Yen Mei ; Liang, Hsiang Fa ; Liu, Chih Peng ; Liu, Ren Shyan ; Shen, Biing Jiun ; Wei, Yau Huei ; Chuang, Chi Mu. / Bypassing the EPR effect with a nanomedicine harboring a sustained-release function allows better tumor control. In: International Journal of Nanomedicine. 2015 ; Vol. 10. pp. 2485-502.
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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({\circledR}), 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.",
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AU - Shyu, Ing Luen

AU - Lu, Maggie

AU - He, Chun Lin

AU - Hsu, Yen Mei

AU - Liang, Hsiang Fa

AU - Liu, Chih Peng

AU - Liu, Ren Shyan

AU - Shen, Biing Jiun

AU - Wei, Yau Huei

AU - Chuang, Chi Mu

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N2 - 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.

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