Cancer-associated thrombus (CAT) impedes delivery of nanoparticles to tumor sites and also inhibits the ability of immune cells to detect and attack these tumors, particularly in advanced tumors with old thrombi. Nattokinase (NK) is an extract from a popular Japanese food, natto, which consists of boiled soybeans fermented with bacteria. Nattokinase exerts strong fibrinolytic and thrombolytic activities and can unblock blood vessels. To deliver NK to thrombus sites in tumors, we modified the surface of NK with polysialic acid (PSA), which formed complexes via electrostatic interactions, resulting in NK-PSA. Particle size and zeta potential of NK-PSA were evaluated, and differential scanning calorimetry, Fourier-transform infrared spectroscopy, and morphological analyses of NK-PSA were performed. To determine the efficacy of the NK-PSA complex on delivery of nanoparticulate drugs, sialic acid-modified doxorubicin liposomes (DOX-SAL) were used as a model drug. In vivo pharmacokinetic and tissue distribution analyses showed that the blood clearance rate of DOX-SAL was significantly enhanced by NK-PSA, and NK-PSA increased accumulation of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide (DiR) labeled SAL (DiR-SAL) in tumors. Analysis of anti-tumor efficacy showed that the combination of NK-PSA and DOX-SAL enhanced anti-tumor activity. These results suggested that NK-PSA combined with DOX-SAL may be an effective strategy to clear CAT and increase the ability of nanoparticles and immune cells to reach tumors.

中文翻译：

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纳豆激酶-聚唾液酸复合物的开发，用于晚期肿瘤治疗。

癌症相关的血栓（CAT）阻碍了纳米颗粒向肿瘤部位的递送，并且还抑制了免疫细胞检测和攻击这些肿瘤的能力，特别是在具有旧血栓的晚期肿瘤中。纳豆激酶（NK）是日本流行食品纳豆的提取物，纳豆由煮沸的大豆经细菌发酵而成。纳豆激酶具有很强的纤维蛋白溶解和血栓溶解活性，可以解除血管阻塞。为了将NK传递到肿瘤中的血栓部位，我们用聚唾液酸（PSA）修饰了NK的表面，该聚唾液酸通过静电相互作用形成复合物，从而产生NK-PSA。评价了NK-PSA的粒径和ζ电位，并进行了差示扫描量热法，傅立叶变换红外光谱法和NK-PSA的形态分析。为了确定NK-PSA复合物对递送纳米颗粒药物的功效，将唾液酸修饰的阿霉素脂质体（DOX-SAL）用作模型药物。体内药代动力学和组织分布分析表明，NK-PSA显着提高了DOX-SAL的血液清除率，并且NK-PSA增加了1,1'-二十八烷基-3,3,3'，3'-四甲基吲哚并花青素的积累碘化物（DiR）标记为肿瘤中的SAL（DiR-SAL）。抗肿瘤功效的分析表明，NK-PSA和DOX-SAL的组合可增强抗肿瘤活性。这些结果表明，NK-PSA结合DOX-SAL可能是清除CAT并提高纳米颗粒和免疫细胞到达肿瘤的能力的有效策略。唾液酸修饰的阿霉素脂质体（DOX-SAL）被用作模型药物。体内药代动力学和组织分布分析表明，NK-PSA显着提高了DOX-SAL的血液清除率，并且NK-PSA增加了1,1'-二十八烷基-3,3,3'，3'-四甲基吲哚并花青素的积累碘化物（DiR）标记为肿瘤中的SAL（DiR-SAL）。抗肿瘤功效的分析表明，NK-PSA和DOX-SAL的组合可增强抗肿瘤活性。这些结果表明，NK-PSA结合DOX-SAL可能是清除CAT并提高纳米颗粒和免疫细胞到达肿瘤的能力的有效策略。唾液酸修饰的阿霉素脂质体（DOX-SAL）被用作模型药物。体内药代动力学和组织分布分析表明，NK-PSA显着提高了DOX-SAL的血液清除率，并且NK-PSA增加了1,1'-二十八烷基-3,3,3'，3'-四甲基吲哚并花青素的积累碘化物（DiR）标记为肿瘤中的SAL（DiR-SAL）。抗肿瘤功效的分析表明，NK-PSA和DOX-SAL的组合可增强抗肿瘤活性。这些结果表明，NK-PSA结合DOX-SAL可能是清除CAT并提高纳米颗粒和免疫细胞到达肿瘤的能力的有效策略。-二十八烷基-3,3,3'，3'-四甲基吲哚并花青碘化物（DiR）标记为肿瘤中的SAL（DiR-SAL）。抗肿瘤功效的分析表明，NK-PSA和DOX-SAL的组合可增强抗肿瘤活性。这些结果表明，NK-PSA结合DOX-SAL可能是清除CAT并提高纳米颗粒和免疫细胞到达肿瘤的能力的有效策略。-二十八烷基-3,3,3'，3'-四甲基吲哚并花青碘化物（DiR）标记为肿瘤中的SAL（DiR-SAL）。抗肿瘤功效的分析表明，NK-PSA和DOX-SAL的组合可增强抗肿瘤活性。这些结果表明，NK-PSA结合DOX-SAL可能是清除CAT并提高纳米颗粒和免疫细胞到达肿瘤的能力的有效策略。