RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题:Tumor tropic delivery of FU.FA@NSs using mesenchymal stem cells for synergistic chemo-photodynamic therapy of colorectal cancer.
Tumor tropic delivery of FU.FA@NSs using mesenchymal stem cells for synergistic chemo-photodynamic therapy of colorectal cancer.
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为克服纳米治疗剂靶向能力和间充质干细胞(MSCs)载药能力的局限性,本研究依托MSCs的肿瘤趋向性与纳米药物递送平台的控释功能相结合,实现化疗药物在肿瘤特异性蓄积并最大限度减少脱靶效应。将含5-氟尿嘧啶(5-FU)的二氧化铈(CeNPs)包覆碳酸钙纳米颗粒(CaNPs),并用亚叶酸(FA)功能化,以开发含药纳米复合材料(Ca.FU.Ce.FA NCs)。随后将NCs与氧化石墨烯(GO)偶联并修饰银纳米颗粒(Ag NPs),形成FU.FA@NS,这是一种合理设计的药物递送系统,具有O 2 生成能力,可缓解肿瘤缺氧以改善光动力治疗。用FU.FA@NSs工程化MSCs,实现了治疗药物在表面膜上的成功负载和长期保留,且对MSCs功能特性的改变最小。在UVA暴露下,将FU.FA@NS.MSCs与CT26细胞共培养,结果显示通过ROS介导的线粒体途径增强了肿瘤细胞凋亡。从MSCs释放的FU.FA@NSs通过网格蛋白介导的内吞途径被CT26细胞有效摄取,并以pH、H 2 O 2 和UVA刺激的方式分布其药物储库。
因此,本研究构建的基于细胞的仿生药物递送平台可被视为结直肠癌靶向化疗-光动力治疗的一种有前景的策略。
To overcome the limitations associated with the targeting abilities of nanotherapeutics and drug loading capacity of mesenchymal stem cells (MSCs), the present study relies on the combination of MSCs tumor tropism with the controlled release function of nano-based drug delivery platforms to achieve tumor-specific accumulation of chemotherapeutics with minimal off-target effects. 5-fluorouracil (5-FU)-containing ceria (CeNPs) coated calcium carbonate nanoparticles (CaNPs) were functionalized with folinic acid (FA) to develop drug-containing nanocomposites (Ca. FU. Ce. FA NCs). NCs were then conjugated with graphene oxide (GO) and decorated with silver nanoparticles (Ag NPs) to form FU.
FA@NS, a rationally designed drug delivery system with O 2 generation capacity that alleviates tumor hypoxia for improved photodynamic therapy. Engineering of MSCs with FU. FA@NSs provided successful loading and long-term retention of therapeutics on the surface membrane with minimal changes to the functional properties of MSCs.
Co-culturing of FU. FA@NS. MSCs with CT26 cells upon UVA exposure revealed enhanced apoptosis in tumor cells through ROS-mediated mitochondrial pathway. FU. FA@NSs released from MSCs were effectively taken up by CT26 cells via a clathrin-mediated endocytosis pathway and distributed their drug depots in a pH, H 2 O 2 , and UVA-stimulated fashion.
Therefore, the cell-based biomimetic drug delivery platform formulated in the current study could be considered a promising strategy for targeted chemo-photodynamic therapy of colorectal cancer.
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