文献：

Ratiometric co-encapsulation and co-delivery of doxorubicin and paclitaxel by tumor-targeted lipodisks for combination therapy of breast cancer

文献链接：

作者：

Chunlai Feng, Haisheng Zhang, Jiaming Chen, Siqi Wang, Yuanrong Xin, Yang Qua,Qi Zhang, Wei Ji, Fumiyoshi Yamashita, Mengjie Ruia,, Ximing Xu

相关产品：

DSPE-PEG-FITC（磷脂-聚乙二醇-FITC）

原文摘要：

Combination therapy is a promising treatment for certain advanced drug-resistant cancers. Although effective inhibition of various tumor cells was reported in vitro, combination treatment requires improvement in vivo due to uncontrolled ratiometric delivery. In this study, a tumor-targeting lipodisk nanoparticle formulation was developed for ratiometric loading and the transportation of two hydrophobic model drugs, doxorubicin (DOX) and paclitaxel (PTX), in one single platform. Furthermore, a slightly acidic pH-sensitive peptide (SAPSP) incorporated into lipodisks effectively enhanced the tumor-targeting and cell internalization. The obtained coloaded lipodisks were approximately 30 nm with a pH-sensitive property. The ratiometric co-delivery of two drugs via lipodisks was confirmed in both the drug-resistant MCF-7/ADR cell line and its parental MCF-7 cell line in vitro, as well as in a tumor-bearing mouse model in vivo compared with a cocktail solution of free drugs. Coloaded lipodisks exerted improved cytotoxicity to tumor cells in culture, particularly to drug-resistant tumor cells at synergistic drug ratios. In an in vivo xenograft mouse model, the anti-tumor ability of co-loaded lipodisks was evidenced by the remarkable inhibitory effect on tumor growth of either MCF-7 or MCF-7/ADR tumors,which may be attributed to the increased and ratiometric accumulation of both drugs in the tumor tissues.Therefore, tumor-specific lipodisks were crucial for the combination treatment of DOX and PTX to completely exert a synergistic anti-cancer effect. It is concluded that for co-loaded lipodisks, cytotoxicity data in vitro could be used to predict their inhibitory activity in vivo, potentially enhancing the clinical outcome of synergistic therapy.

DSPE-PEG-FITC是一种结合了磷脂（DSPE，即二硬脂酰磷脂酰乙醇胺）、聚乙二醇（PEG）和荧光素（FITC）的复合物。DSPE（二硬脂酰磷脂酰乙醇胺）是一种常用的磷脂，自然存在于细胞膜中，能够很好地与生物系统相容。在DSPE-PEG-FITC复合物中，DSPE提供了亲脂性特性，使得整个复合物能够嵌入到细胞膜或脂质体中。PEG（聚乙二醇）是一种亲水性的聚合物，常用于改善化合物的溶解性、稳定性和循环时间。在DSPE-PEG-FITC复合物中，PEG链作为连接桥，将亲脂性的DSPE和亲水性的FITC连接起来，不仅增加了复合物的水溶性，还增强了其生物相容性。PEG的存在还有助于减少复合物被免疫系统识别和清除的可能性，从而延长其在体内的循环时间。FITC（荧光素）是一种常用的荧光染料，具有明亮的绿色荧光和较高的量子产率。在DSPE-PEG-FITC复合物中，FITC作为荧光标记物，使得复合物在紫外光或特定波长的光激发下能够发出绿色荧光。这种荧光特性使得复合物在细胞成像、生物标记和化合物追踪等方面具有应用。基于此，该文献合成脂盘纳米颗粒制剂过程如下：

图：作用机制

空白靶向脂盘由DSPC/DSPEPEG2000/DSPE-PEG-SAPSP按一定摩尔比组成。最初，脂质，包括DSPC、DSPE-PEG2000和DSPE-PEG-SAPSP，被称重并溶解在氯仿中。原料中的总脂质量为缓冲液中；然而，在某些情况下，数量略有变化，以研究最佳的封装效率。然后，将脂质溶液混合，在真空中蒸发，制备脂质膜。获得的脂质膜在 HBS（HEPES缓冲盐水）中水合。使用超声波细胞干扰器将水合样品在冰上进行超声处理。超声处理后，离心，去除探针尖端的金属碎片。最后，将含有SAPSP部分的目标脂盘样品保存在4°C下，直到进一步使用。

在制备共载脂盘之前，将二氯甲烷中的DOX·HCl与过量的三乙胺在黑暗中搅拌，以去除盐酸。然后，将脱盐后的DOX和PTX以适当的摩尔比与氯仿混合，然后加入脂质氯仿溶液。由DSPC/DSPEPEG2000/DSPE-PEG-SAPSP/化合物（DOX + PTX）组成的脂盘的剩余制备工艺与空白脂盘相同。为了纯化负载化合物，获得的脂盘使用Amicon Ultra-50K装置离心超滤去除化合物沉淀。在亚细胞分布研究中，共载脂盘中一半的总脂质被荧光脂质，DSPE-PEG-FITC取代。

图：电镜检测图

结论：

该文献成功合成出了SAPSP肽共载脂盘，这种负载脂盘对培养的tumour细胞具有改善的细胞poison性，特别是对协同化合物比的耐药tumour细胞。在DSPE-PEG-FITC中，FITC作为荧光标记物，使得复合物在紫外光或特定波长的光激发下能够发出绿色荧光，与实验组形成对照。结果表明，这种共载脂盘，有提高效果的可能。