Institute of Biomedical Engineering, Chinese Academy of Medical Sciences & Peking Union Medical College, The Key Laboratory of Biomedical Material of Tianjin, Tianjin 300192, PR China.
Int J Pharm. 2013 May 1;448(1):142-9. doi: 10.1016/j.ijpharm.2013.03.032. Epub 2013 Mar 25.
Folate conjugated amphiphilic polymeric micelles have attracted much attention for active targeted delivery of drugs in folate receptor α (FR-α) positive tumors. However, the efficacy improvement of targeted delivery folate-based nanovehicles was limited by the abundance of FR-α on the surface of tumor cells. Recently, it was found that FR-α expression of Hela cells could be up-regulated by modulators such as dexamethasone, which open a new avenue to enhance the efficiency of targeted delivery from the biological view. In this study, folate-conjugated or plain lipid-core micelles loaded with fluorescent coumarin 6 or mitoxantrone (MTN) were prepared by self-assembly. In addition, FOLR1 mRNA and cell surface FR-α levels were evaluated in Hela cells with dexamethasone treatment. The endocytosis of folate-conjugated or plain micelles loaded with coumarin 6 was examined with confocal microscopy and flow cytometry, which displayed that folate-conjugated micelles can be internalized more efficiently in dexamethasone-treated Hela cells than in normal Hela cells. Moreover, the antitumor activity of folate-conjugated micellar MTN was also improved through up-regulation of FR-α. Therefore, FR-α up-regulation using modulators has great potential to improve the therapeutic efficacy of folate-conjugated nanovehicles in some FR-α positive tumors via receptor-mediated endocytosis.
叶酸偶联两亲性聚合物胶束因其在叶酸受体 α（FR-α）阳性肿瘤中对药物的主动靶向递送而受到广泛关注。然而，靶向递送叶酸基纳米载体的疗效改善受到肿瘤细胞表面 FR-α丰度的限制。最近，研究发现地塞米松等调节剂可上调 Hela 细胞的 FR-α表达，这从生物学角度为提高靶向递送效率开辟了新途径。在本研究中，通过自组装制备了负载荧光香豆素 6 或米托蒽醌（MTN）的叶酸偶联或普通脂质核胶束。此外，用地塞米松处理 Hela 细胞评估 FOLR1 mRNA 和细胞表面 FR-α水平。通过共聚焦显微镜和流式细胞术检查了负载香豆素 6 的叶酸偶联或普通胶束的内吞作用，结果显示，与正常 Hela 细胞相比，地塞米松处理的 Hela 细胞中叶酸偶联胶束的内吞效率更高。此外，通过上调 FR-α，叶酸偶联胶束米托蒽醌的抗肿瘤活性也得到了提高。因此，使用调节剂上调 FR-α 有可能通过受体介导的内吞作用提高叶酸偶联纳米载体在某些 FR-α 阳性肿瘤中的治疗效果。
