Yi Xiaoli, Yan Yue, Shen Xinran, Li Lian, Huang Yuan
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, No. 17, Block 3, South Renmin Road, Chengdu 610041, China.
Pharmaceutics. 2022 Jul 23;14(8):1534. doi: 10.3390/pharmaceutics14081534.
Poor anti-metastasis effects and side-effects remain a challenge for the clinical application of camptothecin (CPT). Mitochondria can be a promising target for the treatment of metastatic tumors due to their vital roles in providing energy supply, upregulating pro-metastatic factors, and controlling cell-death signaling. Thus, selectively delivering CPT to mitochondria appears to be a feasible way of improving the anti-metastasis effect and reducing adverse effects. Here, we established a 2-(dimethylamino) ethyl methacrylate (DEA)-modified -(2-hydroxypropyl) methacrylamide (HPMA) copolymer-CPT conjugate (P-DEA-CPT) to mediate the mitochondrial accumulation of CPT. The mitochondria-targeted P-DEA-CPT could overcome multiple barriers by quickly internalizing into 4T1 cells, then escaping from lysosome, and sufficiently accumulating in mitochondria. Subsequently, P-DEA-CPT greatly damaged mitochondrial function, leading to the reactive oxide species (ROS) elevation, energy depletion, apoptosis amplification, and tumor metastasis suppression. Consequently, P-DEA-CPT successfully inhibited both primary tumor growth and distant metastasis in vivo. Furthermore, our studies revealed that the mechanism underlying the anti-metastasis capacity of P-DEA-CPT was partially via downregulation of various pro-metastatic proteins, such as hypoxia induction factor-1α (HIF-1α), matrix metalloproteinases-2 (MMP-2), and vascular endothelial growth factor (VEGF). This study provided the proof of concept that escorting CPT to mitochondria via a mitochondrial targeting strategy could be a promising approach for anti-metastasis treatment.
喜树碱（CPT）的抗转移效果不佳以及副作用问题仍然是其临床应用面临的一项挑战。线粒体在提供能量供应、上调促转移因子以及控制细胞死亡信号传导等方面发挥着至关重要的作用，因此有望成为转移性肿瘤治疗的靶点。于是，将CPT选择性地递送至线粒体似乎是提高抗转移效果并减少不良反应的一种可行方法。在此，我们制备了一种甲基丙烯酸2-（二甲氨基）乙酯（DEA）修饰的聚（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物-CPT偶联物（P-DEA-CPT），以介导CPT在线粒体中的蓄积。线粒体靶向性的P-DEA-CPT能够通过快速内化进入4T1细胞、随后从溶酶体逃逸并充分蓄积在线粒体中，从而克服多重障碍。随后，P-DEA-CPT极大地破坏了线粒体功能，导致活性氧（ROS）升高、能量耗竭、凋亡放大以及肿瘤转移受到抑制。因此，P-DEA-CPT在体内成功抑制了原发性肿瘤生长和远处转移。此外，我们的研究表明，P-DEA-CPT抗转移能力的潜在机制部分是通过下调各种促转移蛋白，如缺氧诱导因子-1α（HIF-1α）、基质金属蛋白酶-2（MMP-2）和血管内皮生长因子（VEGF）实现的。本研究提供了概念验证，即通过线粒体靶向策略将CPT转运至线粒体可能是一种有前景的抗转移治疗方法。
