Alpha-tocopheryl succinate and doxorubicin-loaded liposomes improve drug uptake and tumor accumulation in a murine breast tumor model.
Alpha-tocopheryl succinate and doxorubicin-loaded liposomes improve drug uptake and tumor accumulation in a murine breast tumor model.
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DOI：
10.1016/j.biopha.2023.115034
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发表时间：
2023-09
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--
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由刚性双层组成的脂质体具有高血浆稳定性;然而，由于释放包封药物以及被肿瘤细胞内化的并发症，它们的功效可能受到挑战。另一方面，融合脂质体可与质膜融合并将包封的材料直接释放到细胞质中。在先前的研究中，开发了由α-生育酚琥珀酸酯（TS）和多柔比星（DOX）组成的融合脂质体（pHSL-TS-DOX）。与商业制剂相比，这些制剂稳定了肿瘤生长并降低了毒性。在本研究中，我们研究了肿瘤中的细胞摄取或DOX积累是否可以证明pHSL-TS-DOX制剂的更好性能。还进行了释放、变形性和DOX血浆浓度研究。pHSL-TS-DOX显示出足够的释放曲线并证明了可变形制剂的特征。来自细胞凋亡、细胞周期和核形态学研究的数据表明，由pHSL-TS-DOX引起的细胞死亡的诱导发生得更快。当施用pHSL-TS-DOX时，观察到更高的DOX细胞摄取和肿瘤蓄积，证明了更好的药物递送能力。因此，更好的DOX摄取以及肿瘤蓄积解释了先前对于该制剂证明的大的抗肿瘤活性。
Liposomes composed of a rigid bilayer have high plasma stability; however, they can be challenged in efficacy due to complications in releasing the encapsulated drug as well as being internalized by the tumor cell. On the other hand, fusogenic liposomes may fuse with the plasmatic membrane and release encapsulated material directly into the cytoplasm. In a previous study, fusogenic liposomes composed of alpha-tocopheryl succinate (TS) and doxorubicin (DOX) were developed (pHSL-TS-DOX). These stabilized tumor growth and reduced toxicity compared to a commercial formulation. In the present study, we investigated whether cellular uptake or DOX accumulation in the tumor could justify the better performance of the pHSL-TS-DOX formulation. Release, deformability, and DOX plasmatic concentration studies were also carried out. pHSL-TS-DOX showed an adequate release profile and demonstrated characteristics of a deformable formulation. Data from apoptosis, cell cycle, and nuclear morphology studies have shown that the induction of cell death caused by pHSL-TS-DOX occurred more quickly. Higher DOX cellular uptake and tumor accumulation were observed when pHSL-TS-DOX was administered, demonstrating better drug delivery capacity. Therefore, better DOX uptake as well as tumor accumulation explain the great antitumor activity previously demonstrated for this formulation.
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