title: Bypassing the EPR effect with a nanomedicine harboring a sustained-release function allows better tumor control.
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.
authors.affiliation: Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yao An
authors.initials: YA
authors.lastname: Shen
authors.affiliation: Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ing Luen
authors.initials: IL
authors.lastname: Shyu
authors.affiliation: Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan.
authors.forename: Maggie
authors.initials: M
authors.lastname: Lu
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chun Lin
authors.initials: CL
authors.lastname: He
authors.affiliation: Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yen Mei
authors.initials: YM
authors.lastname: Hsu
authors.affiliation: Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan.
authors.forename: Hsiang Fa
authors.initials: HF
authors.lastname: Liang
authors.affiliation: Biomedical Technology and Device Research Laboratories, Industrial Technology Research Institute, Hsinchu, Taiwan.
authors.forename: Chih Peng
authors.initials: CP
authors.lastname: Liu
authors.affiliation: Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan ; National PET/Cyclotron Center, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Ren Shyan
authors.initials: RS
authors.lastname: Liu
authors.affiliation: Division of Psychology, Nanyang Technological University, Singapore.
authors.forename: Biing Jiun
authors.initials: BJ
authors.lastname: Shen
authors.affiliation: Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yau Huei
authors.initials: YH
authors.lastname: Wei
authors.affiliation: 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.
authors.forename: Chi Mu
authors.initials: CM
authors.lastname: Chuang
mesh_terms: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D006801:Humans; D050997:Nanomedicine; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D012107:Research Design
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations
keywords: enhanced permeability and retention effect; liposome; ovarian cancer; paclitaxel
references.citation: Ann Oncol. 2004 Mar;15(3):440-9
references.pmid: 14998846
references.citation: Cancer Biomark. 2007;3(4-5):245-50
references.pmid: 17917153
references.citation: Transl Oncol. 2011 Aug;4(4):203-11
references.pmid: 21804915
references.citation: Adv Drug Deliv Rev. 2013 Nov;65(13-14):1763-83
references.pmid: 24120657
references.citation: Oncogene. 2010 Aug 26;29(34):4741-51
references.pmid: 20531305
references.citation: J Clin Oncol. 2005 Nov 1;23(31):7794-803
references.pmid: 16172456
references.citation: Surg Oncol Clin N Am. 2012 Oct;21(4):645-63
references.pmid: 23021722
references.citation: Am J Obstet Gynecol. 1989 Apr;160(4):812-7; discussion 817-9
references.pmid: 2712114
references.citation: Am J Pathol. 2010 Sep;177(3):1053-64
references.pmid: 20651229
references.citation: Nat Rev Cancer. 2009 Apr;9(4):265-73
references.pmid: 19262571
references.citation: Cancer J. 2009 Sep-Oct;15(5):401-5
references.pmid: 19826360
references.citation: Nat Rev Clin Oncol. 2010 Aug;7(8):455-65
references.pmid: 20531380
references.citation: N Engl J Med. 1996 Dec 26;335(26):1950-5
references.pmid: 8960474
references.citation: Pharmacol Rev. 2006 Sep;58(3):621-81
references.pmid: 16968952
references.citation: J Control Release. 2010 Dec 1;148(2):135-46
references.pmid: 20797419
references.citation: Nat Rev Cancer. 2006 Aug;6(8):583-92
references.pmid: 16862189
references.citation: Cancer Cell Int. 2011 Jan 07;11(1):1
references.pmid: 21214935
references.citation: Cancer. 2008 Aug 1;113(3):490-6
references.pmid: 18521923
references.citation: Acta Pharm. 2006 Sep;56(3):311-24
references.pmid: 19831280
references.citation: Nat Rev Clin Oncol. 2010 Feb;7(2):108-15
references.pmid: 20010898
references.citation: Adv Drug Deliv Rev. 2013 Jan;65(1):80-8
references.pmid: 23036224
references.citation: Theranostics. 2013;4(1):81-9
references.pmid: 24396516
references.citation: Gastroenterol Res Pract. 2012;2012:541842
references.pmid: 22888339
references.citation: Nanomedicine (Lond). 2014 Mar;9(3):501-22
references.pmid: 24746193
references.citation: N Engl J Med. 2006 Jan 5;354(1):34-43
references.pmid: 16394300
references.citation: Lancet Oncol. 2003 May;4(5):277-83
references.pmid: 12732164
references.citation: Cancer. 2002 Jan 1;94(1):25-36
references.pmid: 11815957
references.citation: Surg Clin North Am. 2000 Dec;80(6):1631-73
references.pmid: 11140865
references.citation: Cancer Res. 2013 Apr 15;73(8):2412-7
references.pmid: 23423979
references.citation: Cancer Chemother Pharmacol. 2012 Mar;69(3):781-7
references.pmid: 22037881
references.citation: Ann Surg Oncol. 2007 Feb;14(2):484-92
references.pmid: 17054002
references.citation: Ann Surg Oncol. 2007 Oct;14(10):2702-13
references.pmid: 17653801
references.citation: J Clin Oncol. 1999 Oct;17(10):3110-6
references.pmid: 10506606
references.citation: Pharmacol Ther. 2010 Nov;128(2):324-35
references.pmid: 20705093
references.citation: J Pharm Sci. 1961 Oct;50:874-5
references.pmid: 13907269
references.citation: Adv Drug Deliv Rev. 1999 Nov 10;40(1-2):75-87
references.pmid: 10837781
references.citation: Onco Targets Ther. 2013 Sep 30;6:1347-61
references.pmid: 24124379
references.citation: Cancer Res. 2009 Feb 1;69(3):1174-81
references.pmid: 19176391
references.citation: Nat Rev Drug Discov. 2009 Jul;8(7):547-66
references.pmid: 19568282
references.citation: Surg Today. 2013 Jun;43(6):648-53
references.pmid: 22855011
references.citation: Cancer Res. 2010 Jan 15;70(2):440-6
references.pmid: 20068163
references.citation: Nat Rev Cancer. 2012 Feb;12(2):133-43
references.pmid: 22237392
references.citation: J Clin Oncol. 2012 Jun 10;30(17):2055-62
references.pmid: 22547591
references.citation: Cancer Chemother Pharmacol. 1998;41(2):147-54
references.pmid: 9443628
references.citation: Clin Pharmacol Ther. 1993 Aug;54(2):205-18
references.pmid: 8354028
references.citation: Surg Oncol Clin N Am. 2012 Oct;21(4):611-23
references.pmid: 23021719
references.citation: Eur Rev Med Pharmacol Sci. 2012 Jun;16(6):737-42
references.pmid: 22913203
references.citation: Arch Pathol Lab Med. 2004 Dec;128(12):1418-23
references.pmid: 15578887
references.citation: Int J Cancer. 1984 Nov 15;34(5):717-23
references.pmid: 6389375
references.citation: Cancer Res. 1981 Apr;41(4):1311-7
references.pmid: 7214320