EPR-Effect Enhancers Strongly Potentiate Tumor-Targeted Delivery of Nanomedicines to Advanced Cancers: Further Extension to Enhancement of the Therapeutic Effect
Open accessAbstract
For more than three decades, enhanced permeability and retention (EPR)-effect-based nanomedicines have received considerable attention for tumor-selective treatment of solid tumors. However, treatment of advanced cancers remains a huge challenge in clinical situations because of occluded or embolized tumor blood vessels, which lead to so-called heterogeneity of the EPR effect. We previously developed a method to restore impaired blood flow in blood vessels by using nitric oxide donors and other agents called EPR-effect enhancers. Here, we show that two novel EPR-effect enhancers—isosorbide dinitrate (ISDN, Nitrol®) and sildenafil citrate—strongly potentiated delivery of three macromolecular drugs to tumors: a complex of poly(styrene-co-maleic acid) (SMA) and cisplatin, named Smaplatin® (chemotherapy); poly(N-(2-hydroxypropyl)methacrylamide) polymer-conjugated zinc protoporphyrin (photodynamic therapy and imaging); and SMA glucosamine-conjugated boric acid complex (boron neutron capture therapy). We tested these nanodrugs in mice with advanced C26 tumors. When these nanomedicines were administered together with ISDN or sildenafil, tumor delivery and thus positive therapeutic results increased two- to four-fold in tumors with diameters of 15 mm or more. These results confirmed the rationale for using EPR-effect enhancers to restore tumor blood flow. In conclusion, all EPR-effect enhancers tested showed great potential for application in cancer therapy.
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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 [9]
The Introduction (page unavailable) says that vascular clots or thrombi often suppress blood flow in large clinical tumors, limiting the EPR effect; it also links obstructed blood flow to advanced cancers. It does not specifically identify refractory tumors as having this problem, and notes that some human tumors retain a considerable EPR effect. (LLM, conf=0.83)
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 [9]
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References 50 · Cited by 30
- Authors
- Islam, W., Kimura, S., Islam, R., Harada, A., Ono, K., Fang, J., Niidome, T., Sawa, T., & Maeda, H.
- Affiliations
- Kumamoto University (JP)
- Sojo University (JP)
- Tohoku University (JP)
- Corresponding author
- Fang, Jun
- ORCID
- Venue
- Journal of Personalized Medicine
- Publisher
- MDPI AG
- Published
- 2021-05-28
- Volume
- 11
- Issue
- 6
- Pages
- 487
- ISSN
- 2075-4426 (ISSN-L)
- PMC
- PMC8229906
- OpenAlex
- W3165051754
- Cited by
- 30
- References
- 50
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 4 · 2023: 5 · 2022: 9 · 2021: 3
- FWCI
- 1.37
- 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 (29400001, 17016076, 18H04059)
- Japan Science and Technology Agency (AS242Z01542Q)
- Ministry of Health, Labour and Welfare (General 001)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Keywords
- enhanced permeability and retention effect, isosorbide dinitrate, sildenafil, nitric oxide donors, anticancer drug delivery, advanced solid tumors, cisplatin, poly(styrene-co-maleic acid), zinc protoporphyrin, photodynamic therapy, boron neutron capture therapy, C26 colon carcinoma, macromolecular drug delivery
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