文献：Targeted Lipid Nanoparticles Encapsulating Dihydroartemisinin and Chloroquine Phosphate for Suppressing the Proliferation and Liver Metastasis of Colorectal Cancer

文献链接：

作者：Jianqing Peng, Qin Wang, Jia Zhou, Shuli Zhao, Pan Di, Yan Chen, Ling Tao,Qianming Du, Xiangchun Shen and Yi Chen

相关产品：

DSPE-PEG2000 磷脂-聚乙二醇2000

DSPE-PEG2000-cRGD 磷脂-聚乙二醇2000-cRGD肽

原文摘要：Antimalarial drugs Dihydroartemisinin (DHA) and chloroquine phosphate (CQ) exhibit evident anti-cancer

activity, particularly as combination therapy. DHA and CQ combination therapy has been proved to exhibit higher cytotoxic effect in tumor cells and lower toxicity to normal cells than combination of artemisinin derivatives (ARTs) and anticancer chemotherapy drugs. However, different physiochemical properties of DHA and CQ, leading to distinctive in vivo outcomes, considerably limited their synergistic effect in cancer treatment. Herein, we developed a lipid nanoparticle (LNP) for co-delivery of DHA and CQ to inhibit proliferation and metastasis of colorectal cancer. Considering the beneficial effects of acid/reactive oxide species (ROS)-sensitive phospholipids and targeting ligands for colorectal cancer cells, an RGD peptide-modified pH/ROS dualsensitive LNP loaded with DHA and CQ (RLNP/DC) was prepared. It exhibited optimal cytotoxicity and suppression of invasion and metastasis in HCT116 cells in vitro, attributable to irreversible upregulation of intracellular ROS levels, downregulation of VEGF expression, and upregulation of paxillin expression. A mouse model of orthotopic metastasis of colorectal cancer was established to evaluate anti-proliferation and anti-metastasis effects of RLNP/DC in vivo. Thus, an optimized nanoplatform for DHA and CQ combination therapy was developed in this study that offered potential antitumor efficacy against colorectal cancer.

DSPE-PEG2000-cRGD是由DSPE、PEG2000和cRGD组成。DSPE作为磷脂部分，具有出色的两亲性，可在合适条件下自组装形成脂质体等纳米结构。PEG2000的存在改善了材料的亲水性，使整个分子在水相环境中能保持良好的分散状态。cRGD是活性部分，它是一种对整合素具有高亲和力和特异性识别能力的环肽。这使得DSPE-PEG2000-cRGD能够准确地靶向表达特定整合素的细胞或组织，可用于构建靶向tumor细胞的化合物递送系统。DHA和CQ不同的理化性质，导致了不同的体内结果，限制了它们的协同作用。在此，该文献制备了一种RGD肽修饰的pH/ROS双敏感LNP，装载DHA和CQ（RLNP/DC）。制备过程如下：

图：RLNP/DC作用机制示意图

DHA/cq负载LNPs的制备

DHA和CQ共封装的LNPs采用顺序载药过程制备。将SPC、DOPE、DOPC、CO、GT和DHA以一定质量比例溶解在氯仿中。将溶解在乙醇中的DSPE-PEG2000质量比加入到总脂质中。涡旋，使用旋转蒸发器去除有机溶剂，得到脂质薄膜。然后，将硫酸铵溶液，水化，加入到水浴中浸泡。水化溶液超声，然后通过过滤器。因此，获得的LNP/DHA用氯化钠透析。然后，LNP/DHA与CQ溶液以总脂质/CQ质量比在水浴中孵育。通过磷酸盐缓冲盐水（PBS，pH 7.4）透析去除游离CQ，获得LNP/DHA/CQ（LNP/ DC）。此外，采用插入后的方法获得了RGD肽修饰的LNPs。将DSPE-PEG2000- cRGD配体涂在LNP/DHA/CQ表面，水浴，获得RLNP/DC。

图：DHA、CQ、DHA + CQ、LNP/DC、RLNP/DC和RLNP处理24 h后HCT116细胞周期阻滞

结论：DSPE-PEG2000和DSPE-PEG2000-cRGD 参与制备的RGD肽修饰的pH/ROS双敏感LNP，装载DHA和CQ（RLNP/DC）在体外HCT116细胞中表现出细胞有害性和侵袭转移抑制，这是由于细胞内ROS水平上调不可逆，VEGF表达下调，帕西林表达上调。建立cancer 细胞原位转移小鼠模型，评价RLNP/DC在体内的抗转移作用。因此，本研究开发了一种脂质纳米颗粒（LNP），用于共传递DHA和CQ开发了一种优化的DHA和CQ联合应用的纳米平台。