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The 35th Anniversary of the Discovery of EPR Effect: A New Wave of Nanomedicines for Tumor-Targeted Drug Delivery—Personal Remarks and Future Prospects
Article

EPR-Effect Enhancers Strongly Potentiate Tumor-Targeted Delivery of Nanomedicines to Advanced Cancers: Further Extension to Enhancement of the Therapeutic Effect

1
Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
2
BioDynamics Research Foundation, Kumamoto 862-0954, Japan
3
StateArt Inc., Tokyo 103-0012, Japan
4
Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan
5
Faculty of Advanced Science and Technology, Kumamoto University, Kumamoto 860-8555, Japan
6
Tohoku University, Sendai 980-8572, Japan
*
Author to whom correspondence should be addressed.
The author passed away during article revision.
Academic Editor: Stefano Leporatti
J. Pers. Med. 2021, 11(6), 487; https://doi.org/10.3390/jpm11060487
Received: 19 April 2021 / Revised: 25 May 2021 / Accepted: 26 May 2021 / Published: 28 May 2021
(This article belongs to the Special Issue EPR Effect-Based Tumor Targeted Nanomedicine)
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. View Full-Text
Keywords: isosorbide dinitrate; sildenafil citrate; EPR effect; EPR-effect enhancers; heterogeneity of the EPR effect; nitric oxide donors; tumor blood flow isosorbide dinitrate; sildenafil citrate; EPR effect; EPR-effect enhancers; heterogeneity of the EPR effect; nitric oxide donors; tumor blood flow
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MDPI and ACS Style

Islam, W.; Kimura, S.; Islam, R.; Harada, A.; Ono, K.; Fang, J.; Niidome, T.; Sawa, T.; Maeda, H. EPR-Effect Enhancers Strongly Potentiate Tumor-Targeted Delivery of Nanomedicines to Advanced Cancers: Further Extension to Enhancement of the Therapeutic Effect. J. Pers. Med. 2021, 11, 487. https://doi.org/10.3390/jpm11060487

AMA Style

Islam W, Kimura S, Islam R, Harada A, Ono K, Fang J, Niidome T, Sawa T, Maeda H. EPR-Effect Enhancers Strongly Potentiate Tumor-Targeted Delivery of Nanomedicines to Advanced Cancers: Further Extension to Enhancement of the Therapeutic Effect. Journal of Personalized Medicine. 2021; 11(6):487. https://doi.org/10.3390/jpm11060487

Chicago/Turabian Style

Islam, Waliul, Shintaro Kimura, Rayhanul Islam, Ayaka Harada, Katsuhiko Ono, Jun Fang, Takuro Niidome, Tomohiro Sawa, and Hiroshi Maeda. 2021. "EPR-Effect Enhancers Strongly Potentiate Tumor-Targeted Delivery of Nanomedicines to Advanced Cancers: Further Extension to Enhancement of the Therapeutic Effect" Journal of Personalized Medicine 11, no. 6: 487. https://doi.org/10.3390/jpm11060487

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