title: Enhanced Efficacy of Doxorubicin by microRNA-499-Mediated Improvement of Tumor Blood Flow.
abstract: 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.
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. s14803@u-shizuoka-ken.ac.jp.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Okamoto
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. asai@u-shizuoka-ken.ac.jp.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asai
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. rorange0805@gmail.com.
authors.forename: Sho
authors.initials: S
authors.lastname: Ryu
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. h.ando@tokushima-u.ac.jp.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ando
authors.affiliation: Nippon Fine Chemical Co. Ltd., 5-1-1 Umei, Takasago, Hyogo 676-0074, Japan. n-maeda@nipponseika.com.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Maeda
authors.affiliation: Department of Life and Materials Engineering, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan. takedewa@nitech.ac.jp.
authors.forename: Takehisa
authors.initials: T
authors.lastname: Dewa
authors.affiliation: Department of Medical Biochemistry, University of Shizuoka School of Pharmaceutical Sciences, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan. oku@u-shizuoka-ken.ac.jp.
authors.forename: Naoto
authors.initials: N
authors.lastname: Oku
keywords: cancer therapy; gene delivery; liposomes; miR-499; microRNA; tumor blood perfusion