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J. Clin. Med. 2016, 5(1), 10;

Enhanced Efficacy of Doxorubicin by microRNA-499-Mediated Improvement of Tumor Blood Flow

Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Nippon Fine Chemical Co. Ltd., 5-1-1 Umei, Takasago, Hyogo 676-0074, Japan
Department of Life and Materials Engineering, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan
Author to whom correspondence should be addressed.
Academic Editors: Takahiro Ochiya and Ryou-u Takahashi
Received: 30 November 2015 / Revised: 25 December 2015 / Accepted: 14 January 2016 / Published: 19 January 2016
(This article belongs to the Special Issue MicroRNAs: Novel Biomarkers and Therapeutic Targets for Human Cancers)
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Genetic therapy using microRNA-499 (miR-499) was combined with chemotherapy for the advanced treatment of cancer. Our previous study showed that miR-499 suppressed tumor growth through the inhibition of vascular endothelial growth factor (VEGF) production and subsequent angiogenesis. In the present study, we focused on blood flow in tumors treated with miR499, since some angiogenic vessels are known to lack blood flow. Tetraethylenepentamine-based polycation liposomes (TEPA-PCL) were prepared and modified with Ala-Pro-Arg-Pro-Gly peptide (APRPG) for targeted delivery of miR-499 (APRPG-miR-499) to angiogenic vessels and tumor cells. The tumor blood flow was significantly improved, so-called normalized, after systemic administration of APRPG-miR-499 to Colon 26 NL-17 carcinoma–bearing mice. In addition, the accumulation of doxorubicin (DOX) in the tumors was increased by pre-treatment with APRPG-miR-499. Moreover, the combination therapy of APRPG-miR-499 and DOX resulted in significant suppression of the tumors. Taken together, our present data indicate that miR-499 delivered with APRPG-modified-TEPA-PCL normalized tumor vessels, resulting in enhancement of intratumoral accumulation of DOX. Our findings suggest that APRPG-miR-499 may be a therapeutic, or a combination therapeutic, candidate for cancer treatment. View Full-Text
Keywords: microRNA; miR-499; cancer therapy; gene delivery; liposomes; tumor blood perfusion microRNA; miR-499; cancer therapy; gene delivery; liposomes; tumor blood perfusion

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Okamoto, A.; Asai, T.; Ryu, S.; Ando, H.; Maeda, N.; Dewa, T.; Oku, N. Enhanced Efficacy of Doxorubicin by microRNA-499-Mediated Improvement of Tumor Blood Flow. J. Clin. Med. 2016, 5, 10.

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