The DOI matches its Crossref record; 87 of the 87 references it cites were found in a registry or an index.
The 35th Anniversary of the Discovery of EPR Effect: A New Wave of Nanomedicines for Tumor-Targeted Drug Delivery—Personal Remarks and Future Prospects
Open accessAbstract
This Special Issue on the enhanced permeability and retention (EPR) effect commemorates the 35th anniversary of its discovery, the original 1986 Matsumura and Maeda finding being published in Cancer Research as a new concept in cancer chemotherapy. My review here describes the history and heterogeneity of the EPR effect, which involves defective tumor blood vessels and blood flow. We reported that restoring obstructed tumor blood flow overcomes impaired drug delivery, leading to improved EPR effects. I also discuss gaps between small animal cancers used in experimental models and large clinical cancers in humans, which usually involve heterogeneous EPR effects, vascular abnormalities in multiple necrotic foci, and tumor emboli. Here, I emphasize arterial infusion of oily formulations of nanodrugs into tumor-feeding arteries, which is the most tumor-selective drug delivery method, with tumor/blood ratios of 100-fold. This method is literally the most personalized medicine because arterial infusions differ for each patient, and drug doses infused depend on tumor size and anatomy in each patient. Future developments in EPR effect-based treatment will range from chemotherapy to photodynamic therapy, boron neutron capture therapy, and therapies for free radical diseases. This review focuses on our own work, which stimulated numerous scientists to perform research in nanotechnology and drug delivery systems, thereby spawning a new cancer treatment era.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, many clinical cancers such as late-stage tumors and refractory tumors are associated with poor blood flow due to the coagulation and thrombi formation exhibiting poor EPR effect [7,8,9,10,11,12].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [7]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The EPR effect can be enhanced by modifying vascular intermediaries such as angiotensin II, nitroglycerin or NO, CO, and enzyme inhibitors [7,8,9,10].”
From Approaches to Improve EPR-Based Drug Delivery for Cancer Therapy and Diagnosis (2023) · cites this paper as [7]
Experimental — accuracy not yet measuredIn the citing paper
“However, because tumor blood flow and vascular permeability are significantly varied from each other, the EPR effect may not be beneficial for all solid tumors.194”
From Smart nanoparticles for cancer therapy (2023) · cites this paper as [194]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Matsumura, Y., & Maeda, H. (1986) · PubMed · Cited by 6,781
Self-citationAnalysis of nanoparticle delivery to tumours
Wilhelm, S., Tavares, A. J., Dai, Q., Ohta, S., Audet, J., Dvorak, H. F., & Chan, W. C. W. (2016) · Nature Reviews Materials · doi:10.1038/natrevmats.2016.14 · Cited by 5,218
Fang, J. Q., Nakamura, H., & Maeda, H. (2010) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2010.04.009 · Cited by 3,573
Self-citationMaeda, H. (2001) · Advances in Enzyme Regulation · doi:10.1016/s0065-2571(00)00013-3 · Cited by 2,495
Self-citationMaeda, H., Nakamura, H., & Fang, J. (2013) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2012.10.002 · Cited by 2,376
Self-citationPrabhakar, U., Maeda, H., Jain, R. K., Sevick-Muraca, E. M., Zamboni, W. C., Farokhzad, O. C., Barry, S. T., Gabizón, A., Grodzinski, P. A., & Blakey, D. C. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-4561 · Cited by 1,493
Self-citationGabizón, A., Catane, R., Uziely, B., Kaufman, B., Safra, T., Cohen, R., Martin, F., Huang, A., & Barenholz, Y. (1994) · PubMed · Cited by 1,382
Maeda, H. (2015) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.01.002 · Cited by 1,179
Self-citationTumor-Selective Delivery of Macromolecular Drugs via the EPR Effect: Background and Future Prospects
Maeda, H. (2010) · Bioconjugate Chemistry · doi:10.1021/bc100070g · Cited by 997
Self-citationMacromolecular therapeutics in cancer treatment: The EPR effect and beyond
Maeda, H. (2012) · Journal of Controlled Release · doi:10.1016/j.jconrel.2012.04.038 · Cited by 815
Self-citation
Flagged first, then by citations
Research works printed but not linked: 2
- Pasut, G., and Zalipsky, S. (2020). Overcoming barriers for tumor-targeted drug delivery: The power of macromo-lecular anticancer drugs with the EPR effect and the modulation of vascular physiology. Polymer-Protein Conjugation: From PEGylation and Beyond, Elsevier.
- Maeda, 2015, Great expectations for innovative PDT and tumor imaging using fluorescing nanophotosensitizers that utilizes EPR effect, JSMI Rep., 9, 3
Cited by
Sorted by citations
Items 101–167 of 167
Wu, S., & Wang, C. (2025) · International Journal of Nanomedicine · doi:10.2147/ijn.s522247 · Cited by 5
Canale, J. J., Fernández‐Quiroz, D., Teran‐Saavedra, N. G., Diaz-Galvez, K. R., Gallegos-Tabanico, A., Burgara-Estrella, A., Sarabia-Sainz, H. M., Guzmán-Partida, A. M., Robles–Burgueño, M. D. R., Vázquez–Moreno, L., et al. (2022) · Acta Biochimica Polonica · doi:10.18388/abp.2020_5975 · Cited by 5
Islam, W., Tsutsuki, H., Rahman, A., Harada, A., Zhang, T., Ono, K., Islam, R., Hossen, F., Niidome, T., Sawa, T., et al. (2023) · ACS Applied Polymer Materials · doi:10.1021/acsapm.3c02042 · Cited by 4
pH-Dependent Non-Covalent Release of Chemotherapy from Carriers
Leng, Q., Anand, A., & Mixson, A. J. (2024) · Discovery Medicine · doi:10.24976/discov.med.202436182.42 · Cited by 4
Wu, J. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12111802 · Cited by 4
Trejo-Teniente, I., Jaramillo-Loranca, B. E., Hernández, G. V., Villanueva-Ibáñez, M., Tovar-Jiménez, X., Venegas, P. N. O., & Tapia-Ramı́rez, J. (2024) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2024.1378601 · Cited by 4
Photodynamic Therapy Using IR-783 Liposomes for Advanced Tongue and Breast Cancers in Humans
Komura, Y., Kimura, S., Hirasawa, Y., Katagiri, T., Takaura, A., Yoshida, F., Fukuro, S., Muranishi, H., Imataki, O., & Homma, K. (2024) · Journal of Functional Biomaterials · doi:10.3390/jfb15120363 · Cited by 3
Ma, T., Mao, Z., Xue, B., Cao, Y., & Sun, W. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27021076 · Cited by 3
Chiral noble-metal nanomaterials: Chiral origins and biomedical applications
Zhou, B., Zhang, Y., Lei, Q., Zhang, Z., Wang, R., Liu, P., Xu, X., Jia, T., & Cheng, J. (2026) · Smart Materials in Medicine · doi:10.1016/j.smaim.2026.01.001 · Cited by 3
Jia, B., Zhong, Y., Zhai, D., Pang, J., Sha, B., Li, N., Li, B., Liang, W., & Bian, W. (2026) · RSC Advances · doi:10.1039/d5ra08760k · Cited by 3
Tiwary, P., Oswal, K., Varghese, R., & Gupta, P. K. (2026) · Journal of Nanotheranostics · doi:10.3390/jnt7020011 · Cited by 4
Galen, J. E., & Pham, T. (2022) · Medical Research Archives · doi:10.18103/mra.v10i7.2895 · Cited by 3
Puchkova, Y. A., Sedush, N. G., Ivanenko, A. D., Shuvatova, V. G., Posypanova, G. A., & Чвалун, С. Н. (2023) · Mendeleev Communications · doi:10.1016/j.mencom.2023.04.033 · Cited by 3
Anti-tumor activity of silymarin nanoliposomes in combination with iron: In vitro and in vivo study
Doagooyan, M., Alavizadeh, S. H., Sahebkar, A., Houshangi, K., Khoddamipour, Z., & Gheybi, F. (2023) · International Journal of Pharmaceutics X · doi:10.1016/j.ijpx.2023.100214 · Cited by 3
Nanoparticle-Mediated Cancer Chemotherapy
Khan, M. (2024) · Springer eBooks · doi:10.1007/978-981-97-3545-7_9 · Cited by 3
Islam, W., Tsutsuki, H., Ono, K., Harada, A., Shinozaki, K., Niidome, T., Fang, J. Q., & Sawa, T. (2022) · ACS Applied Bio Materials · doi:10.1021/acsabm.2c00883 · Cited by 3
Characterization and Efficacy of a Nanomedical Radiopharmaceutical for Cancer Treatment
Mattisson, I. Y., Bäckström, S., Ekengard, E., Lekmeechai, S., Liu, Y., Paris, J., Petoral, R. M., Sydoff, M., Hansen, M., & Axelsson, O. (2023) · ACS Omega · doi:10.1021/acsomega.2c06755 · Cited by 3
Parshina, Y. P., Kovylina, T. A., Konev, A. N., Belikov, A. A., Baber, P. O., Komarova, A. D., Romaeva, E. A., & Bochkarev, L. N. (2022) · Russian Journal of General Chemistry · doi:10.1134/s1070363222120167 · Cited by 3
Simmons, R., Kameyama, H., Kubota, S., Sun, Y., Langenheim, J. F., Ajeeb, R., Shao, T. S., Ricketts, S. D., Annan, A. C., Stratemeier, N., et al. (2024) · Breast Cancer Research and Treatment · doi:10.1007/s10549-024-07410-x · Cited by 3
Iki, N. (2025) · Analytical Sciences · doi:10.1007/s44211-025-00740-w · Cited by 3
Bochkarev, L. N., Parshina, Y. P., Komarova, A. D., Baber, P. O., Kovylina, T. A., Konev, A. N., Mozherov, A. M., Shcheslavskiy, V. I., & Shirmanova, M. V. (2024) · Journal of Organometallic Chemistry · doi:10.1016/j.jorganchem.2024.123349 · Cited by 2
Liu, T., Zhang, D., Wang, X., Li, J., Zhang, H., Tang, K., & Wang, L. (2025) · Chemical Engineering Journal · doi:10.1016/j.cej.2025.167856 · Cited by 3
Multifunctional Metal Complexes for Cancer Theranostics
Iki, N. (2024) · Nanomedicine and nanotoxicology · doi:10.1007/978-981-97-5288-1_6 · Cited by 2
Tripathi, A., Vaishnaw, B., Jaishwal, P., Samal, P. K., Verma, A., & Singh, N. (2025) · Current Materials Science · doi:10.2174/0126661454366845250618053301 · Cited by 2
Nanoscintillators as Next-Generation Radiotherapeutics: Bridging Physics, Chemistry, and Oncology
Bedregal-Portugal, K., Mercier, A., Stelse‐Masson, S., Aubrun, C., Elleaume, H., Verry, C., & Bulin, A. (2025) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.5c00249 · Cited by 2
Yanazume, S., Fang, J. Q., Islam, R., Gao, S., & Kobayashi, H. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12050814 · Cited by 2
Peptide Nanostructured Materials as Drug Delivery Carriers
Bellotto, O., & Marchesan, S. (2023) · Springer eBooks · doi:10.1007/978-3-031-29360-3_12 · Cited by 2
pH modification of gel mobility shift improves polyplex selection In Vivo
Leng, Q., Anand, A., & Mixson, A. J. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.150566 · Cited by 2
From conventional therapy to novel nano-based approaches. A focus on prostate cancer
Chiaverini, L., Ferraro, G., Leo, R. D., Barresi, E., Mendola, D. L., Bartoli, F., Famlonga, L., Satriano, C., Faviana, P., Zucchi, A., et al. (2025) · Nanomedicine · doi:10.1080/17435889.2025.2501513 · Cited by 2
Poly(amino acid)-based design principle for pH-responsive tumor delivery
Takemoto, H., Umeno, T., & Oba, M. (2026) · OpenNano · doi:10.1016/j.onano.2026.100301 · Cited by 1
Ponchelle, M., Kulesza, A., Zieliński, M., Cieszykowska, I., Huber, G., Gravel, E., Pruszyński, M., & Doris, E. (2026) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2026.127219 · Cited by 1
Cho, U., Pu, J., Sharma, A., Song, J., You, J. H., Kim, Y., Im, P. W., Park, H. W., Moon, H. E., Myeong, H. S., et al. (2026) · Molecular Cancer · doi:10.1186/s12943-026-02736-0 · Cited by 2
Nanotechnology in vaccines and personalized medicine
Azevedo, M. S. P., & Patri, A. K. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-824010-6.00043-5 · Cited by 1
Abdulla, A. E., Gader, T. K. M., Omer, M. O. W., Gouda, A. E., Mamdouh, S., & Shemis, M. A. (2024) · Advances in Nanoparticles · doi:10.4236/anp.2024.133004 · Cited by 1
Liposomes in Anticancer Strategies
Izbińska, P., Szlauer, W., & Obłąk, E. (2024) · Current Cancer Therapy Reviews · doi:10.2174/0115733947312894240930110609 · Cited by 1
Rizzuti, B. (2022) · Journal of Personalized Medicine · doi:10.3390/jpm12101662 · Cited by 1
Datalyst - data node center as a catalyst for urban development
Eriksson, I., & Nilsson, F. U. (2012) · Chalmers Publication Library (Chalmers University of Technology)
Kashiwagi, H., Kawabata, S., Yoshimura, K., Fukuo, Y., Kanemitsu, T., Takeuchi, K., Hiramatsu, R., Nishimura, K., Kawai, K., Takata, T., et al. (2021) · Research Square · doi:10.21203/rs.3.rs-832070/v1
Biotinylated polymeric micelles based on amphiphilic poly(HPMA) block copolymers
Wang, Y. (2022) · Utrecht University Repository (Utrecht University) · doi:10.33540/1553
Rumyantseva, V. D., Shilov, I. P., & Ivanov, A. V. (2024) · Meditsinskaya Fizika · doi:10.52775/1810-200x-2024-103-3-83-91
Toward Polymeric Room Temperature Acid Generators
Roberts, J. W., Lanzendorf, A. N., Aguilar-Romero, J. E., Paterson, M. L., Jalomo, C. A., Morado, E. G., & Zimmerman, S. C. (2024) · ChemistryOpen · doi:10.1002/open.202400289
Popova, T. V., Van, M., Kurochkin, T. N., Tsyrempilov, S. A., Zakharova, O. D., Silnikov, V. N., & Godovikova, T. S. (2025) · Russian Journal of Bioorganic Chemistry · doi:10.1134/s1068162025010194
Ding, Y., Wei, P., Xia, D., Deng, M., Zhang, Y., Li, M., Yan, Z., & Chen, T. (2025) · Current Drug Delivery · doi:10.2174/0115672018351085250212080829 · Cited by 1
Nonaka, M., Hirakata, M., Sakai, C., Tomikawa, E., Izawa, A., Nishi, T., Koga, Y., Takahashi, K., Shimozono, R., Ohshima, K., et al. (2025) · Cardiovascular Toxicology · doi:10.1007/s12012-025-09994-2 · Cited by 1
Özgenç, E., Gündoğdu, E., Başpınar, Y., Kara, Ü., & Kılıcoglu, O. (2025) · Research Square · doi:10.21203/rs.3.rs-7177199/v1
Emerging Nanotechnologies Transforming Cancer Therapeutic
Doshi, A., Singh, L., & Shah, B. (2025) · Series in bioengineering · doi:10.1007/978-981-95-0457-2_12
Rudy, S. S., Canale, J. J., Sarabia-Sainz, J. A., Guzmán-Partida, A. M., Burgara-Estrella, A., Silva‐Campa, E., Ángulo-Molina, A., Montiel‐Herrera, M., Flores‐Ramírez, N., Zavala‐Rivera, P., et al. (2025) · Nanomaterials · doi:10.3390/nano15191538
Advanced strategies to improve the accumulation of nanotherapeutics in tumor
Choudhury, S., Tamang, R., Singh, V., Saad, M., Yadav, P., & Talegaonkar, S. (2025) · Elsevier eBooks · doi:10.1016/b978-0-443-33343-9.00012-0 · Cited by 1
Bista, S., Sharma, M., Paudel, S., Ranjit, Y., Singh, A., Rawal, S., Joshi, P. R., & Adhikari, S. P. (2026) · Advances in Materials Science and Engineering · doi:10.1155/amse/9988654
Cellulose nanocrystal carrier with schiff base-based responsive drug release
Li, C., Chu, Y., Zhang, S., Zhang, W., Chen, Y., Zhang, L., Xiao, H., & Wu, W. (2026) · Colloids and Surfaces A Physicochemical and Engineering Aspects · doi:10.1016/j.colsurfa.2026.139652
Zhang, X., Yang, L., He, X., Zhao, M., Fang, Z., Xu, G., Duan, Z., & Luo, K. (2026) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2026.03.050
Lehot, V. (2021) · theses.fr (ABES) · doi:10.70675/718d38b9z5733z42a0z857azc52585ec3dbc
Développement d'un ciblage moléculaire et d'un ciblage nanoparticulaire des dysfonctions vasculaires
Louis, B. (2022) · theses.fr (ABES) · doi:10.70675/4213c176z0905z4638z8db3z7ea83befc80b
Mittelheisser, V. (2024) · theses.fr (ABES) · doi:10.70675/92b9630bz16afz4843z93caz705680f2ac69
Bochkarev, L. N., Parshina, Y. P., Baranov, E. V., Kovylina, T. A., Konev, A. N., Komarova, A. D., Elagin, V. V., & Shirmanova, M. V. (2026) · Russian Journal of Coordination Chemistry · doi:10.1134/s1070328425601633
Pabisa, L., Mayasari, E., Raya, I., Mandey, F., & Mubaraq, W. (2026) · Polymer Bulletin · doi:10.1007/s00289-026-06472-9
Aptamer-Functionalized Liposome Delivery System Based on Multifunctional Microreactor Design
Guo, J., Chen, W., Wang, B., Peng, S., Wu, Y., Lin, Y., Lin, R., & Chen, D. (2026) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.6c09467
Overview of Nanoparticles as Radiopharmaceutical Vectors
Xie, H., Pappas, A. C., Kempe, K., & Goos, J. A. C. M. (2026) · Springer eBooks · doi:10.1007/978-3-032-26476-3_10
Recent advancement in the codelivery of proteins and small-molecule drugs for targeted therapy
Salehi, S., & Naghib, S. M. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-33639-3.00012-x
Skonieczna, B., Nazarko, N., Godlewska, E., Wasiluk, N., Czech, E. K., Wilczewska, A. Z., Regulska, E., Car, H., & Niemirowicz-Laskowska, K. (2026) · Journal of Nanobiotechnology · doi:10.1186/s12951-026-04801-8
Manganese Ion‐Based NanoPlatforms for Tumor Theranostics
Xiangzhou, L., Xie, W., Jin, X., Sun, T. R., Shang, Y., Deng, Z., & Peng, H. (2026) · Advanced Healthcare Materials · doi:10.1002/adhm.71519
Zhang, G., Quan, H., Zhang, Y., Wang, M., & Wang, J. (2026) · Analytica Chimica Acta · doi:10.1016/j.aca.2026.346147
Jiang, G., Wang, G., Tao, J., & Feng, W. (2026) · Beni-Suef University Journal of Basic and Applied Sciences · doi:10.1186/s43088-026-00822-2
Xing, H., Dong, H., Guo, C., Wang, Z., Zou, Y., Wang, X., & He, R. (2026) · Small · doi:10.1002/smll.75718
Tumor-homing peptides in precision oncology
Ma, G., Derkaoui, D. K., SENHADJI, R., Karoyan, P., & Poyet, J. (2026) · Journal of Controlled Release · doi:10.1016/j.jconrel.2026.115360
Ultrasound triggered microbubbles enhance the diagnosis and therapy of colorectal cancer
Wang, Q., Gong, Y., Zao, S., Sun, F., Wang, J., & Lu, Y. (2026) · Discover Nano · doi:10.1186/s11671-026-04872-4
Wang, Q., Li, H., Zhang, Y., Zhou, Y., Ran, S., & Li, H. (2026) · Nanoscale · doi:10.1039/d6nr02257j
Metadata
- Authors
- Maeda, H.
- Affiliations
- Tohoku University (JP)
- Corresponding author
- Maeda, Hiroshi
- ORCID
- Maeda, Hiroshi
- Venue
- Journal of Personalized Medicine
- Publisher
- MDPI AG
- Published
- 2021-03-22
- Volume
- 11
- Issue
- 3
- Pages
- 229
- ISSN
- 2075-4426 (ISSN-L)
- PMC
- PMC8004895
- OpenAlex
- W3138405372
- Cited by
- 167
- References
- 87
- Citations by year
- 2026: 24 · 2025: 23 · 2024: 29 · 2023: 35 · 2022: 40 · 2021: 15
- FWCI
- 2.06
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Personalized Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Japan Society for the Promotion of Science (18H04059, 29400001)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- enhanced permeability and retention effect, anticancer drug delivery, nanomedicine, tumor perfusion, tumor vasculature, arterial infusion, tumor emboli, tumor necrosis, photodynamic therapy, boron neutron capture therapy, cancer chemotherapy, personalized medicine
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
