抑制NADPH氧化酶- ros信号--使用透明质酸纳米颗粒克服癌-症中的辐射耐药治疗

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文件名称：	抑制NADPH氧化酶- ros信号--使用透明质酸纳米颗粒克服癌-症中的辐射耐药治疗
公司名称：	PhD Technology LLC
下载次数：	344
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ABSTRACT: Upregulation of NADPH oxidases (NOXs) in cancer cells leads to chronic increase in intracellular reactive oxygen species (ROS) and adaptation to a high ROS level for cell survival and, thereby, low sensitivity to radiotherapy. To overcome resistance to radiotherapy, we have developed a bioactive and CD44 targeted hyaluronic acid nanoparticle encapsulated with an NOX inhibitor, GKT831 (HANP/ GKT831). We found that HANP/GKT831 had stronger inhibitory effects on ROS generation and cell proliferation than that of GKT831 alone in cancer cells. Systemic delivery of HANP/GKT831 led to the targeted accumulation in breast cancer patient derived xenograft (PDX) tumors in nude mice. Importantly, the combination of systemic delivery of HANP/ GKT831 with a low dose of local radiotherapy significantly enhanced tumor growth inhibition in breast cancer PDX models. Our results showed that HANP/GKT831 primed tumor cells to radiation-induced DNA damage and cell death by downregulation of DNA repair function and oncogenic signal pathways. METHODS/EXPERIMENTAL Preparation of Hyaluronic Acid Nanoparticle Carrying GKT831 (HANP/GKT831). HANP/GKT831 nanocomplexes were produced according to our established protocol with minor modifications42 (Figure 2A). Sodium hyaluronic acid (HA, 234 kDa) was purchased from Lifecore Biomedical Company. HA was first converted to the tetrabutylammonium (TBA) salt of HA according to previously reported methods. The HA-TBA was then chemically modified with 5β-cholanic acid (CA) in the presence of 1- ethyl-3(3-(dimethylamino) propyl)carbodiimide (EDC) and N hydroxysuccinimide (NHS) at 60 °C in dimethyl sulfoxide (DMSO) (Sigma-Aldrich) to produce HA-CA. After dialysis against methanol/ultrapure water (1:1, v/v) and then ultrapure water for 4− 12 h, HA-CA was lyophilized and stored at 4 °C in the dark until further use. Next, 80 mg of HA-CA conjugates were dissolved in 14 mL of distilled water and subjected to a high-pressure homogenizer (D-3L, PhD Technology) for 5 min to form HA nanoparticles P(HANPs). Hydrophobic GKT 831 was loaded to HANP via a high pressure homogenizer at a ratio of 10 mg GKT831/40 mg of HANP. Thirty milligrams of GKT831 (MedKoo Biosciences #522357) dissolved in 1 mL of DMSO was added dropwise into the solution containing 120 mg of HANP and then circulated for an additional 5 min in the homogenizer. HANP/GKT831 nanocomplex was then dialyzed for 8 h in distilled water to remove free drugs and organic solvents. Finally, HANP/GKT831 was lyophilized into white powder and kept at 4 °C. 欢迎下载全文，了解更多。
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