Enhanced Permeability and Retention (EPR) Effect for Anticancer Nanomedicine Drug Targeting
Abstract
Effective cancer therapy remains one of the most challenging tasks to the scientific community, with little advancement on overall cancer survival landscape during the last two decades. A major limitation inherent to most conventional anticancer chemotherapeutic agents is their lack of tumor selectivity. One way to achieve selective drug targeting to solid tumors is to exploit abnormalities of tumor vasculature, namely hypervascularization, aberrant vascular architecture, extensive production of vascular permeability factors stimulating extravasation within tumor tissues, and lack of lymphatic drainage. Due to their large size, nano-sized macromolecular anticancer drugs administered intravenously (i.v.) escape renal clearance. Being unable to penetrate through tight endothelial junctions of normal blood vessels, their concentration builds up in the plasma rendering them long plasma half-life. More importantly, they can selectively extravasate in tumor tissues due to its abnormal vascular nature. Overtime the tumor concentration will build up reaching several folds higher than that of the plasma due to lack of efficient lymphatic drainage in solid tumor, an ideal application for EPR-based selective anticancer nanotherapy. Indeed, this selective high local concentration of nano-sized anticancer drugs in tumor tissues has proven superior in therapeutic effect with minimal side effects in both preclinical and clinical settings.
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The thermal effect, mechanical effect and the radiation force generated by ultrasound enhance the transient tissue permeability and are the reasons for stimulating the release of carrier drugs.
“The thermal effect, mechanical effect and the radiation force generated by ultrasound enhance the transient tissue permeability and are the reasons for stimulating the release of carrier drugs.179”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [179]
Cites
Tumor angiogenesis: therapeutic implications
Sherwood, L. M., Parris, E. E., & Folkman, J. (1971) · New England Journal of Medicine · doi:10.1056/nejm197111182852108 · Cited by 10,187 · see citing works
Angiogenesis in cancer, vascular, rheumatoid and other disease
Folkman, J. (1995) · Nature Medicine · doi:10.1038/nm0195-27 · Cited by 7,627 · see citing works
Matsumura, Y., & Maeda, H. (1986) · PubMed · Cited by 6,771 · see citing works
Dougherty, T. J., Gomer, C. J., Henderson, B. W., Jori, G., Kessel, D., Korbelik, M., Moan, J., & Peng, Q. (1998) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/90.12.889 · Cited by 4,716 · see citing works
Gomer, C. J. (1988) · Cited by 4,169 · see citing works
Transplacental Carcinogenesis by Stilbestrol
Folkman, J. (1971) · New England Journal of Medicine · doi:10.1056/nejm197108122850711 · Cited by 2,640 · see citing works
Exploiting the enhanced permeability and retention effect for tumor targeting
Iyer, A. K., Khaled, G., Fang, J., & Maeda, H. (2006) · Drug Discovery Today · doi:10.1016/j.drudis.2006.07.005 · Cited by 1,846 · see citing works
Openings Between Defective Endothelial Cells Explain Tumor Vessel Leakiness
Hashizume, H., Baluk, P., Morikawa, S., McLean, J. W., Thurston, G., Roberge, S., Jain, R. K., & McDonald, D. M. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)65006-7 · Cited by 1,689 · see citing works
Nozawa, H., Chiu, C. W., & Hanahan, D. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0601807103 · Cited by 926 · see citing works
Noguchi, Y., Wu, J., Duncan, R., Strohalm, J., Ulbrich, K., Akaike, T., & Maeda, H. (1998) · Japanese Journal of Cancer Research · doi:10.1111/j.1349-7006.1998.tb00563.x · Cited by 470 · see citing works
Okamoto, T., Akaike, T., Sawa, T., Miyamoto, Y., van der Vliet, A., & Maeda, H. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102417200 · Cited by 466 · see citing works
Yuan, F., Salehi, H. A., Boucher, Y., Vasthare, U. S., Tuma, R. F., & Jain, R. K. (1994) · PubMed · Cited by 463 · see citing works
Seymour, L. W., Miyamoto, Y., Maeda, H., Brereton, M., Strohalm, J., Ulbrich, K., & Duncan, R. (1995) · European Journal of Cancer · doi:10.1016/0959-8049(94)00514-6 · Cited by 337 · see citing works
Greish, K. F., Fang, J. Q., Inutsuka, T., Nagamitsu, A., & Maeda, H. (2003) · Clinical Pharmacokinetics · doi:10.2165/00003088-200342130-00002 · Cited by 277 · see citing works
Self-citationSuzuki, M., Hori, K., Abe, I., Saito, S., & Sato, H. (1981) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/67.3.663 · Cited by 268 · see citing works
Wu, J., Akaike, T., & Maeda, H. (1998) · PubMed · Cited by 212 · see citing works
SMA–doxorubicin, a new polymeric micellar drug for effective targeting to solid tumours
Greish, K. F., Sawa, T., Fang, J. Q., Akaike, T., & Maeda, H. (2004) · Journal of Controlled Release · doi:10.1016/j.jconrel.2004.03.027 · Cited by 183 · see citing works
Self-citationMicrovascular architecture of experimental colon tumors in the rat.
Skinner, S. A., Tutton, P. J. M., & O’Brien, P. E. (1990) · PubMed · Cited by 179 · see citing works
Chen, B., Pogue, B. W., Luna, J. M., Hardman, R. L., Hoopes, P. J., & Hasan, T. G. (2006) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-05-1673 · Cited by 175 · see citing works
Maeda, H., Matsumura, Y., & Kato, H. (1988) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)37555-0 · Cited by 128 · see citing works
Microvessel quantification and its possible relation with liver metastasis in colorectal cancer
Tomisaki, S., Ohno, S., Ichiyoshi, Y., Kuwano, H., Maehara, Y., & Sugimachi, K. (1996) · Cancer · doi:10.1002/(sici)1097-0142(19960415)77:8 · Cited by 118 · see citing works
Li, C. J., Miyamoto, Y., Kojima, Y., & Maeda, H. (1993) · British Journal of Cancer · doi:10.1038/bjc.1993.179 · Cited by 96 · see citing works
Bradykinin and nitric oxide in infectious disease and cancer
Maeda, H., Akaike, T., Wu, J., Noguchi, Y., & Sakata, Y. (1996) · Immunopharmacology · doi:10.1016/0162-3109(96)00063-x · Cited by 70 · see citing works
Tanaka, S., Akaike, T., Wu, J., Fang, J. Q., Sawa, T., Ogawa, M., Beppu, T., & Maeda, H. (2003) · Journal of drug targeting · doi:10.1080/1061186031000086072 · Cited by 59 · see citing works
Cancer Neovascularization and Proinflammatory Microenvironments
Furuya, M., & Yonemitsu, Y. (2008) · Current Cancer Drug Targets · doi:10.2174/156800908784533481 · Cited by 30 · see citing works
Meyer, R. E., Shan, S., DeAngelo, J. D., et al. (1995) · British Journal of Cancer · doi:10.1038/bjc.1995.228 · Cited by 30 · see citing works
Enhanced Permeability and Retention (EPR) Effect and Tumor-Selective Delivery of Anticancer Drugs
Greish, K. F., Iyer, A. K., Fang, J. Q., et al. (2006) · IMPERIAL COLLEGE PRESS eBooks · doi:10.1142/9781860948039_0003 · Cited by 25 · see citing works
Self-citationOhtani, H., Sato, H., Iga, T., Kotaki, H., & Sawada, Y. (1999) · Biopharmaceutics & Drug Disposition · doi:10.1002/(sici)1099-081x(199903)20:2 · Cited by 10 · see citing works
Nagamitsu, A., Inuzuka, T., Greish, K. F., & Maeda, H. (2007) · Drug Delivery System · doi:10.2745/dds.22.510 · Cited by 6 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Smart nanoparticles for cancer therapy
Sun, L., Liu, H., Ye, Y., Lei, Y., Islam, R., Tan, S., Tong, R., Miao, Y.-B., & Cai, L. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01642-x · Cited by 1,073 · see citing works
Layer-by-Layer Nanoparticles with a pH-Sheddable Layer for<i>in Vivo</i>Targeting of Tumor Hypoxia
Poon, Z., Chang, D., Zhao, X., & Hammond, P. T. (2011) · ACS Nano · doi:10.1021/nn200876f · Cited by 343 · see citing works
Zi, Y., Yang, K., He, J., Wu, Z., Liu, J., & Zhang, W. (2022) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2022.114449 · Cited by 268 · see citing works
Xin, L., Gao, J., Zheng, Z., Chen, Y., Lv, S., Zhao, Z., Yu, C., Yang, X., & Zhang, R. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.648187 · Cited by 203 · see citing works
Aptamer-guided nanomedicines for anticancer drug delivery
Alshaer, W., Hillaireau, H., & Fattal, E. (2018) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2018.09.011 · Cited by 187 · see citing works
Ahn, J., Miura, Y., Yamada, N., Chida, T., Liu, X., Kim, A., Sato, R., Tsumura, R., Koga, Y., Yasunaga, M., et al. (2015) · Biomaterials · doi:10.1016/j.biomaterials.2014.10.069 · Cited by 147 · see citing works
Subbiah, V., Grilley-Olson, J. E., Combest, A. J., Sharma, N., Tran, R. H., Bobe, I., Osada, A., Takahashi, K., Balkissoon, J., Camp, A., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-1114 · Cited by 118 · see citing works
Ho, Y. T., Kamm, R. D., & Kah, J. C. Y. (2018) · Nanoscale · doi:10.1039/c8nr02393j · Cited by 102 · see citing works
Comparative investigations on in vitro serum stability of polymeric micelle formulations
Miller, T., Rachel, R., Besheer, A., Uezguen, S., Weigandt, M., & Goepferich, A. (2012) · Pharmaceutical Research · doi:10.1007/s11095-011-0555-x · Cited by 69 · see citing works
Nanodelivery Systems for Nucleic Acid Therapeutics in Drug Resistant Tumors
Iyer, A. K., Duan, Z., & Amiji, M. M. (2014) · Molecular Pharmaceutics · doi:10.1021/mp500024p · Cited by 55 · see citing works
Novel EPR-enhanced strategies for targeted drug delivery in pancreatic cancer: An update
Mohammadzadeh, V., Rahiman, N., Hosseinikhah, S. M., Barani, M., Rahdar, A., Jaafari, M. R., Sargazi, S., Zirak, M. R., Pandey, S., Bhattacharjee, R., et al. (2022) · Journal of Drug Delivery Science and Technology · doi:10.1016/j.jddst.2022.103459 · Cited by 50 · see citing works
Daman, Z., Montazeri, H., Azizi, M., Rezaie, F., Ostad, S. N., Amini, M., & Gilani, K. (2015) · Pharmaceutical Research · doi:10.1007/s11095-015-1737-8 · Cited by 28 · see citing works
Cheng, C.-C., Huang, J.-J., Lee, A.-W., Huang, S.-Y., Huang, C.-Y., & Lai, J.-Y. (2019) · ACS Applied Bio Materials · doi:10.1021/acsabm.9b00146 · Cited by 25 · see citing works
- Authors
- Greish, K.
- Affiliations
- University of Utah (US)
- Corresponding author
- Greish, Khaled
- ORCID
- Greish, Khaled
- Venue
- Methods in Molecular Biology
- Publisher
- Humana Press
- Published
- 2010
- Volume
- 624
- Pages
- 25-37
- ISSN
- 1064-3745 (ISSN-L)
- 1940-6029
- OpenAlex
- W2273495465
- Cited by
- 841
- References
- 29
- Citations by year
- 2026: 12 · 2025: 30 · 2024: 43 · 2023: 44 · 2022: 77 · 2021: 84 · 2020: 108 · 2019: 93 · 2018: 68 · 2017: 61 · 2016: 52 · 2015: 54 · 2014: 52 · 2013: 24 · 2012: 17
- FWCI
- 25.80
- Type
- book chapter
- Language
- en
- Open access
- closed
- Locations
- Methods in molecular biology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- enhanced permeability and retention effect, cancer nanomedicine, tumor targeting, extravasation, tumor selectivity, nanoparticle drug delivery, lymphatic drainage, tumor hypervascularization, nanomedicine
- MeSH terms
- Animals, Antineoplastic Agents, Doxorubicin, Drug Screening Assays, Antitumor, Male, Maleates, Micelles, Models, Biological, Neoplasms, Permeability, Polystyrenes, Tissue Distribution, Drug Delivery Systems, Nanomedicine, Mice
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