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Augmentation of the Enhanced Permeability and Retention Effect with Nitric Oxide-Generating Agents Improves the Therapeutic Effects of Nanomedicines
W. Islam, J. Fang, T. Imamura, T. Etrych, V. Subr, K. Ulbrich, H. Maeda,
Language English Country United States
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
NV16-28594A
MZ0
CEP Register
Digital library NLK
Full text - Article
NLK
Free Medical Journals
from 2001 to 1 year ago
Open Access Digital Library
from 2001-11-01
Open Access Digital Library
from 2001-11-01
- MeSH
- Arginine pharmacology MeSH
- Nitric Oxide Donors pharmacology MeSH
- Doxorubicin analogs & derivatives pharmacology MeSH
- Hydroxyurea pharmacology MeSH
- Macromolecular Substances pharmacology MeSH
- Disease Models, Animal MeSH
- Mice MeSH
- Neoplasms blood supply pathology MeSH
- Nanoparticles chemistry MeSH
- Nanomedicine * MeSH
- Nitroglycerin pharmacology MeSH
- Nitric Oxide biosynthesis MeSH
- Permeability MeSH
- Rats, Sprague-Dawley MeSH
- Antineoplastic Agents pharmacology MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Enhanced permeability and retention (EPR) effect-based nanomedicine is a promising strategy for successful anticancer therapy. The EPR effect is based on tumor blood flow. Because advanced large tumors, as frequently seen in clinical settings, are heterogeneous, with regions of defective vasculature and blood flow, achieving the desired tumor drug delivery is difficult. Here, we utilized the EPR effect to increase drug delivery. To augment the EPR effect for improved therapeutic effects of nanomedicine, we exploited vascular mediators-the nitric oxide (NO) generators nitroglycerin (NG), hydroxyurea, and l-arginine. These compounds generate NO in tumors with relatively high selectivity. Using different nanosized drugs in our protocol significantly increased (1.5-2 times) delivery of nanomedicines to different solid tumor models, along with markedly improving (2-3-fold) the antitumor effects of these drugs. Also, in 7,12-dimethylbenz[a]anthracene-induced advanced end-stage breast cancer, often seen in clinical settings, 2 mg/kg polymer-conjugated pirarubicin (P-THP) with NG (0.2 mg/mouse) showed better effects than did 5 mg/kg P-THP, and 5 mg/kg P-THP used with NG resulted in cures or stable tumors (no tumor growth) for up to 120 days. Moreover, in a murine autochthonous azoxymethane/dextran sulfate sodium-induced colon cancer model, NO donors markedly improved the therapeutic effects of P-THP even after just one injection, results that were comparable with those achieved with three weekly P-THP treatments. These findings strongly suggest the potential usefulness of NO donors as EPR effect enhancers to improve the therapeutic efficacy of nanomedicines.
Department of Microbiology Graduate School of Medical Sciences Kumamoto University Kumamoto Japan
Faculty of Pharmaceutical Sciences Sojo University Kumamoto Japan
Institute of Macromolecular Chemistry Czech Academy of Sciences Prague Czech Republic
References provided by Crossref.org
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- $a Enhanced permeability and retention (EPR) effect-based nanomedicine is a promising strategy for successful anticancer therapy. The EPR effect is based on tumor blood flow. Because advanced large tumors, as frequently seen in clinical settings, are heterogeneous, with regions of defective vasculature and blood flow, achieving the desired tumor drug delivery is difficult. Here, we utilized the EPR effect to increase drug delivery. To augment the EPR effect for improved therapeutic effects of nanomedicine, we exploited vascular mediators-the nitric oxide (NO) generators nitroglycerin (NG), hydroxyurea, and l-arginine. These compounds generate NO in tumors with relatively high selectivity. Using different nanosized drugs in our protocol significantly increased (1.5-2 times) delivery of nanomedicines to different solid tumor models, along with markedly improving (2-3-fold) the antitumor effects of these drugs. Also, in 7,12-dimethylbenz[a]anthracene-induced advanced end-stage breast cancer, often seen in clinical settings, 2 mg/kg polymer-conjugated pirarubicin (P-THP) with NG (0.2 mg/mouse) showed better effects than did 5 mg/kg P-THP, and 5 mg/kg P-THP used with NG resulted in cures or stable tumors (no tumor growth) for up to 120 days. Moreover, in a murine autochthonous azoxymethane/dextran sulfate sodium-induced colon cancer model, NO donors markedly improved the therapeutic effects of P-THP even after just one injection, results that were comparable with those achieved with three weekly P-THP treatments. These findings strongly suggest the potential usefulness of NO donors as EPR effect enhancers to improve the therapeutic efficacy of nanomedicines.
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