The 35th Anniversary of the Discovery of EPR Effect: A New Wave of Nanomedicines for Tumor-Targeted Drug Delivery—Personal Remarks and Future Prospects
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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.
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Many clinical cancers such as late-stage and refractory tumors are associated with poor blood flow due to coagulation and thrombi formation, exhibiting poor EPR effect.
“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]
Section 1.3 says large advanced tumors often have occluded or embolized vessels and describes poor blood flow or weak EPR effects in some human cancers. Section 3.1 says the EPR effect is often reduced in clinical settings when blood flow is impaired. The copy does not specifically establish coagulation and thrombus formation as the cause or identify refractory tumors as a group with poor EPR effects. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe EPR effect can be enhanced by modifying vascular intermediaries such as angiotensin II, nitroglycerin or NO, CO, and enzyme inhibitors.
“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]
Section 1.3 (page unavailable) identifies angiotensin II–induced high blood pressure as an EPR-effect enhancer. Section 3.1 (page unavailable) lists nitroglycerin and angiotensin-converting enzyme inhibitors among enhancers, but the retrieved passages do not establish CO or NO themselves as enhancers; searches for those terms did not resolve that gap. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBecause tumor blood flow and vascular permeability are significantly varied from each other, the EPR effect may not be beneficial for all solid tumors.
“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]
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- 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 · 2012: 1
- 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 ›
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