Enhanced Efficacy of Doxorubicin by microRNA-499-Mediated Improvement of Tumor Blood Flow.
Enhanced Efficacy of Doxorubicin by microRNA-499-Mediated Improvement of Tumor Blood Flow.
复制标题
DOI：
10.3390/jcm5010010
复制
发表时间：
2016-01-19
影响因子：
3.9
通讯作者：
Oku N
中科院分区：
文献类型：
--
作者：
Okamoto A;Asai T;Ryu S;Ando H;Maeda N;Dewa T;Oku N
使用microRNA-499 （miR-499）的基因治疗与化疗联合用于癌症的晚期治疗。我们之前的研究表明，miR-499通过抑制血管内皮生长因子（VEGF）的产生和随后的血管生成来抑制肿瘤生长。在目前的研究中，我们关注的是miR499治疗肿瘤的血流量，因为已知一些血管生成血管缺乏血流量。制备了基于四乙基苯胺的多阳离子脂质体（TEPA-PCL），并用Ala-Pro-Arg-Pro-Gly肽（APRPG）修饰，用于靶向递送miR-499 （APRPG-miR-499）至血管生成血管和肿瘤细胞。在给结肠26 NL-17荷瘤小鼠全身给予APRPG-miR-499后，肿瘤血流量明显改善，所谓正常化。此外，用APRPG-miR-499预处理后，肿瘤中阿霉素（DOX）的积累增加。此外，APRPG-miR-499与DOX联合治疗可显著抑制肿瘤。综上所述，我们目前的数据表明，miR-499与aprpg修饰的tepa - pcl归一化的肿瘤血管一起递送，导致肿瘤内DOX积累增强。我们的研究结果表明，APRPG-miR-499可能是一种治疗或联合治疗癌症的候选药物。
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.