Enhancing Docetaxel Delivery to Multidrug-Resistant Cancer Cells with Albumin-Coated Nanocrystals.
Enhancing Docetaxel Delivery to Multidrug-Resistant Cancer Cells with Albumin-Coated Nanocrystals.
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DOI：
10.1021/acs.molpharmaceut.7b00783
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发表时间：
2018-01-29
影响因子：
4.9
通讯作者：
Yeo Y
中科院分区：
文献类型：
--
作者：
Gad SF;Park J;Park JE;Fetih GN;Tous SS;Lee W;Yeo Y
水溶性差的抗癌药物如多西他赛（DTX）的静脉内递送由于低生物利用度和与增溶赋形剂相关的毒性而具有挑战性。胶体纳米颗粒被用作替代载体，但低载药量和循环不稳定性限制了其临床转化。为了解决这些挑战，使用Pluronic F127作为中间稳定剂和白蛋白作为功能性表面改性剂来制备DTX纳米晶体（NC），这在以前被发现在生产小而稳定的NC中是有效的。我们假设白蛋白包被的DTX NC（DTX-F-alb）将在含血清的介质中保持稳定，以便有效地利用增强的渗透性和保留效果。此外，表面结合的白蛋白以其天然形式可能通过与白蛋白结合蛋白（例如酸性且富含半胱氨酸的分泌蛋白（SPARC））的相互作用来促进NC的细胞转运。DTX-F-alb NC呈片状结构，平均长度、宽度和厚度分别为284 ± 96 nm、173 ± 56 nm和40 ± 8 nm，在浓度大于10 µg/mL的50%血清溶液中保持稳定。DTX-F-alb和未配制（游离）DTX的细胞毒性和细胞摄取进行了比较，在三个细胞系具有不同的表达水平和DTX敏感性。虽然游离DTX的摄取高度依赖于DTX敏感性，但DTX-F-alb处理导致DTX的细胞水平相对一致。游离DTX比DTX-F-alb更有效地进入药物敏感的B16 F10和SKOV-3细胞，具有一致的细胞毒性作用。与此相反，多药耐药NCI/ADR-RES细胞摄取DTX-F-alb比游离DTX随时间的推移，并响应于前者更好。这种差异因SPARC敲除而缩小。NCI/ADR-RES细胞的高α-淀粉酶表达水平、白蛋白对α-淀粉酶的已知亲和力以及α-淀粉酶敲低的相反作用支持DTX-F-alb在进入NCI/ADR-RES细胞中利用了表面结合的白蛋白-α-淀粉酶相互作用。白蛋白包被的NC系统是一种很有前途的制剂，用于将疏水性抗癌药物递送到多药耐药肿瘤。
Intravenous delivery of poorly water-soluble anticancer drugs such as docetaxel (DTX) is challenging due to the low bioavailability and the toxicity related to solubilizing excipients. Colloidal nanoparticles are used as alternative carriers, but low drug loading capacity and circulation instability limit their clinical translation. To address these challenges, DTX nanocrystals (NCs) were prepared using Pluronic F127 as an intermediate stabilizer and albumin as a functional surface modifier, which were previously found to be effective in producing small and stable NCs. We hypothesize that the albumin-coated DTX NCs (DTX-F-alb) will remain stable in serum-containing medium so as to effectively leverage the enhanced permeability and retention effect. In addition, the surface-bound albumin, in its native form, may contribute to cellular transport of NCs through interactions with albumin binding proteins such as Secreted protein acidic and rich in cysteine (SPARC). DTX-F-alb NCs showed sheet-like structure with an average length, width, and thickness of 284 ± 96 nm, 173 ± 56 nm, and 40 ± 8 nm and remained stable in 50% serum solution at a concentration greater than 10 µg/mL. Cytotoxicity and cellular uptake of DTX-F-alb and unformulated (free) DTX were compared on three cell lines with different levels of SPARC expression and DTX sensitivity. While the uptake of free DTX was highly dependent on DTX sensitivity, DTX-F-alb treatment resulted in relatively consistent cellular levels of DTX. Free DTX was more efficient in entering drug-sensitive B16F10 and SKOV-3 cells than DTX-F-alb, with consistent cytotoxic effects. In contrast, multidrug-resistant NCI/ADR-RES cells took up DTX-F-alb more than free DTX with time and responded better to the former. This difference was reduced by SPARC knockdown. The high SPARC expression level of NCI/ADR-RES cells, the known affinity of albumin for SPARC and the opposing effect of SPARC knockdown support that DTX-F-alb have exploited the surface-bound albumin-SPARC interaction in entering NCI/ADR-RES cells. Albumin-coated NC system is a promising formulation for the delivery of hydrophobic anticancer drugs to multidrug-resistant tumors.
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4.9
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