Evidence for Delivery of Abraxane via a Denatured-Albumin Transport System
Evidence for Delivery of Abraxane via a Denatured-Albumin Transport System
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DOI：
10.1021/acsami.1c03065
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发表时间：
2021-04-21
影响因子：
9.5
通讯作者：
Ishida, Tatsuhiro
中科院分区：
文献类型：
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作者：
Hama, Maichi;Ishima, Yu;Ishida, Tatsuhiro
Abraxane是一种白蛋白结合的紫杉醇纳米颗粒制剂，优于传统的紫杉醇制剂，因为它对不可切除的胰腺癌有更好的疗效。先前的报道表明，Abraxane比传统紫杉醇制剂的疗效更好，可能是由于其通过血管内皮细胞表面的白蛋白受体Gp60进行转运。Abraxane的肿瘤蓄积增加也是由肿瘤基质中分泌的富含半胱氨酸的蛋白酸引起的。然而，Abraxane的摄取机制仍然知之甚少。在这项研究中，我们证明了Abraxane的传递途径与内源性白蛋白的传递途径不同。我们的研究结果表明，在内皮细胞或肿瘤细胞的内吞过程中，内源性白蛋白的摄取被Gp60途径抑制剂抑制。相比之下，abraxane衍生的HSA摄取受Gp60途径抑制剂的影响较小，但变性白蛋白受体抑制剂显著降低。总之，这些数据表明，abraxane衍生的HSA通过不同于正常内源性白蛋白的机制进入内皮细胞或肿瘤细胞。这些关于变性白蛋白通过不同于先天白蛋白的gp家族蛋白的不同细胞转运途径的新数据，揭示了Abraxane的肿瘤传递机制和抗肿瘤活性，并为开发一种通过变性白蛋白受体的新型白蛋白药物传递策略提供了新的科学依据。
Abraxane, an albumin-bound paclitaxel nanoparticle formulation, is superior to conventional paclitaxel preparations because it has better efficacy against unresectable pancreatic cancer. Previous reports suggest that this better efficacy of Abraxane than conventional paclitaxel preparation is probably due to its transport through Gp60, an albumin receptor on the surface of vascular endothelial cells. The increased tumor accumulation of Abraxane is also caused by the secreted protein acid and rich in cysteine in the tumor stroma. However, the uptake mechanism of Abraxane remains poorly understood. In this study, we demonstrated that the delivery of Abraxane occurred via different receptor pathways from that of endogenous albumin. Our results showed that the uptake of endogenous albumin was inhibited by a Gp60 pathway inhibitor in the process of endocytosis through endothelial cells or tumor cells. In contrast, the uptake of Abraxane-derived HSA was less affected by the Gp60 pathway inhibitor but significantly reduced by denatured albumin receptor inhibitors. In conclusion, these data indicate that Abraxane-derived HSA was taken up into endothelial cells or tumor cells by a mechanism different from normal endogenous albumin. These new data on distinct cellular transport pathways of denatured albumin via gp family proteins different from those of innate albumin shed light on the mechanisms of tumor delivery and antitumor activity of Abraxane and provide new scientific rationale for the development of a novel albumin drug delivery strategy via a denatured albumin receptor.