PMID- 30232144 OWN - NLM STAT- MEDLINE DCOM- 20190910 LR - 20200930 IS - 1538-8514 (Electronic) IS - 1535-7163 (Linking) VI - 17 IP - 12 DP - 2018 Dec TI - Augmentation of the Enhanced Permeability and Retention Effect with Nitric Oxide-Generating Agents Improves the Therapeutic Effects of Nanomedicines. PG - 2643-2653 LID - 10.1158/1535-7163.MCT-18-0696 [doi] AB - 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. CI - (c)2018 American Association for Cancer Research. FAU - Islam, Waliul AU - Islam W AD - Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. FAU - Fang, Jun AU - Fang J AD - Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan. FAU - Imamura, Takahisa AU - Imamura T AD - Department of Molecular Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. FAU - Etrych, Tomas AU - Etrych T AD - Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic. FAU - Subr, Vladimir AU - Subr V AD - Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic. FAU - Ulbrich, Karel AU - Ulbrich K AD - Institute of Macromolecular Chemistry, Czech Academy of Sciences, Prague, Czech Republic. FAU - Maeda, Hiroshi AU - Maeda H AD - Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. maedabdr@sweet.ocn.ne.jp. AD - BioDynamics Research Foundation, Kumamoto, Japan. AD - Osaka University School of Medicine, Osaka, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180919 PL - United States TA - Mol Cancer Ther JT - Molecular cancer therapeutics JID - 101132535 RN - 0 (Antineoplastic Agents) RN - 0 (Macromolecular Substances) RN - 0 (Nitric Oxide Donors) RN - 31C4KY9ESH (Nitric Oxide) RN - 80168379AG (Doxorubicin) RN - 94ZLA3W45F (Arginine) RN - D58G680W0G (pirarubicin) RN - G59M7S0WS3 (Nitroglycerin) RN - X6Q56QN5QC (Hydroxyurea) SB - IM MH - Animals MH - Antineoplastic Agents/pharmacology MH - Arginine/pharmacology MH - Disease Models, Animal MH - Doxorubicin/analogs & derivatives/pharmacology MH - Female MH - Hydroxyurea/pharmacology MH - Macromolecular Substances/pharmacology MH - Male MH - Mice MH - *Nanomedicine MH - Nanoparticles/chemistry MH - Neoplasms/blood supply/pathology MH - Nitric Oxide/*biosynthesis MH - Nitric Oxide Donors/pharmacology MH - Nitroglycerin/pharmacology MH - Permeability MH - Rats, Sprague-Dawley EDAT- 2018/09/21 06:00 MHDA- 2019/09/11 06:00 CRDT- 2018/09/21 06:00 PHST- 2018/06/25 00:00 [received] PHST- 2018/09/12 00:00 [revised] PHST- 2018/09/12 00:00 [accepted] PHST- 2018/09/21 06:00 [pubmed] PHST- 2019/09/11 06:00 [medline] PHST- 2018/09/21 06:00 [entrez] AID - 1535-7163.MCT-18-0696 [pii] AID - 10.1158/1535-7163.MCT-18-0696 [doi] PST - ppublish SO - Mol Cancer Ther. 2018 Dec;17(12):2643-2653. doi: 10.1158/1535-7163.MCT-18-0696. Epub 2018 Sep 19.