2025-02-17 作者：ZJ 来源：文献：Ultrasound Triggered Conversion of Porphyrin/Camptothecin-Fluoroxyuridine Triad Microbubbles into Nanoparticles Overcomes Multidrug Resistance in Colorectal Cancer
文献链接：https://xueshu.baidu.com/usercenter/paper/show?paperid=1b7g04c0ne4402h02s7s0ju0j7453201&site=xueshu_se
作者：Min Chen, Xiaolong Liang , Chuang Gao, Ranran Zhao, Nisi Zhang, Shumin Wang, Wen Chen, Bo Zhao, Jinrui Wang, Zhifei Dai
相关产品：
DSPE-PEG2000 二硬脂酰磷脂酰乙醇胺-聚乙二醇2000
Cholesterol 胆固醇
原文摘要：Multidrug resistance remains one of the main obstacles to efficient chemotherapy of
colorectal cancer. Herein, an efficient combination therapeutic strategy is proposed based on porphyrin/camptothecin-floxuridine triad microbubbles (PCF-MBs) with high drug loading contents, which own highly stable co-delivery drug combinations and no premature release. The triad PCF-MBs can act not only as a contrast agent for ultrasound (US) /fluorescence bi-modal imaging but also a multi-modal therapeutic agent for synergistic chemo-photodynamic combination therapy. Upon local ultrasound exposure under the guidance of ultrasound imaging, in situ conversion of PCF-MBs into porphyrin/camptothecin-floxuridine nanoparticles (PCF-NPs) leads to high accumulation of chemo-drugs and photosensitizer in tumor due to the induced
high permeability of the capillary wall and cell membrane temporarily viasonoporation effect,greatly reducing the risk of systemic exposure. Most importantly, it was found that the PCF-MBs mediated photodynamic therapy could significantly reduce the expression of adenosine-triphosphate (ATP)-binding cassette sub-family G member 2 (ABCG2), which is responsible for the drug resistance in chemotherapy, resulting in a prominent intracellular camptothecin increase. In vivo experiments revealed that the PCF-MBs in combination of ultrasound and laser irradiation could achieve a 90% tumor inhibition rate of HT-29 cancer with no recurrence. Therefore, such triad PCF-MBs based combination therapeutic strategy shows great promise for overcoming drug resistance of colorectal cancer and other cancers.
DSPE-PEG2000是一种由亲水性的聚乙二醇（PEG，分子量约2000）与疏水性的二硬脂酰磷脂酰乙醇胺（DSPE）通过共价键连接而成。DSPE的疏水长链赋予了它与疏水性物质良好的亲和性，能有效包裹脂溶性化合物等成分；而PEG2000链段则展现出良好的亲水性，使整个分子在水性环境中具有良好的溶解性和稳定性。它具有生物相容性，在体内不易引发免疫排斥反应。同时，DSPE-PEG2000可用于构建多种化合物递送系统，如脂质体和胶束。其PEG链还可进行进一步修饰，连接靶向分子实现主动靶向给药，连接成像标记用于化合物追踪。该文献提出了一种基于卟啉/喜树碱-氟尿嘌呤三联体微泡（PCF-MBs）的策略，载药含量高，具有高稳定的共递送化合物组合，无过早释放。三联征PCF-MBs可以作为超声（US）/荧光双峰成像的造影剂。PCF-MBs介导的光动力应用可以降低三磷酸腺苷（ATP）结合ABCG2的表达，过程如下：
图：PCF-MBs与PGL卟啉接枝脂质和喜树碱-氟尿苷偶联物的自组装示意图
PCF-MBs的合成
通过稳定PFC气芯，制备了三元微气泡外壳由CF、PGL、1,2-二硬脂酰-sn-甘油-3-磷酸胆碱（DSPC）、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000（DSPE-PEG2000）和不同摩尔比的胆固醇组成。在PCF-MBs的设计中，胆固醇作为小分子填补卟啉环刚性结构之间的空间间隙，从而稳定壳层。DSPE-PEG2000作为空间稳定剂，因为指向连续介质，阻止了聚结稳定微气泡。为了调节PCF-MBs的体内稳定性，通过改变CF的摩尔百分比，制备了三种PCF-MBs的配方。
图：PCF-MBs介导-光动力联合应用。
结论：CF摩尔率对DSPC、DSPE-PEG2000、胆固醇参与制备的PCF-MBs的稳定性有影响。PCF-MB（30% CF）具有较高的微泡产率，浓度为1.90×109 MBs/ml，但其载药含量相对较低。对于PCF-MB（50% CF），当浓度为0.70×109 MBs/ml时，CF含量越高，微泡产量较低。然而，PCF-MB（40% CF）具有较高的微泡产量，浓度为1.02×109 MBs/ml，载药含量较高（4.5%卟啉，14.3% FUDR和20.2% CPT）。CF能够形成一个非常浓缩的单层，阻止极气体从核心逸入水介质，而DSPE-PEG2000引入微泡壳阻止PCF-MBs的聚集。
