Niclosamide-conjugated polypeptide nanoparticles inhibit Wnt signaling and colon cancer growth.
Niclosamide-conjugated polypeptide nanoparticles inhibit Wnt signaling and colon cancer growth.
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DOI：
10.1039/c7nr01973d
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发表时间：
2017-08-31
期刊：
影响因子：
6.7
通讯作者：
Chen W
中科院分区：
文献类型：
--
作者：
Bhattacharyya J;Ren XR;Mook RA;Wang J;Spasojevic I;Premont RT;Li X;Chilkoti A;Chen W
Wnt活性异常是导致包括癌症在内的许多疾病的主要机制。以前，我们曾报道驱虫药氯硝柳胺(NIC)抑制WNT/β-连环蛋白信号转导，抑制结肠癌细胞生长。尽管NIC的药代动力学特性适合作为驱虫剂使用，但其低溶解度、低生物利用度和低全身暴露限制了其在治疗全身疾病方面的有效性。为了克服这些限制，我们将NIC偶联到重组嵌合多肽(CP)上，并将CP-NIC偶联物自发地自组装成亚100 nm的近单分散纳米颗粒。与用游离NIC给药相比，静脉注射CP-NIC纳米粒可作为NIC的前药物，显著增加NIC的暴露。与NIC相比，CP-NIC在人结肠癌异种移植模型中提高了抗肿瘤活性。由于NIC具有多种生物活性，CP-NIC可用于治疗多种疾病，包括癌症、细菌和病毒感染、II型糖尿病、NASH和NAFLD。疏水药物NIC(紫色三角形)附着到CP(黑链)上会触发自组装成圆柱形纳米颗粒。
Abnormal Wnt activity is a major mechanism responsible for many diseases, including cancer. Previously, we reported that the anthelmintic drug Niclosamide (NIC) inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth. Although the pharmacokinetic properties of NIC are appropriate for use as an anthelmintic agent, its low solubility, low bioavailability and low systemic exposure limit its usefulness in treating systemic diseases. To overcome these limitations, we conjugated NIC to recombinant chimeric polypeptides (CPs), and the CP-NIC conjugate spontaneously self-assembled into sub-100 nm near-monodisperse nanoparticles. CP-NIC nanoparticles delivered intravenously act as a pro-drug of NIC to dramatically increase exposure of NIC compared to dosing with free NIC. CP-NIC improved anti-tumor activity compared to NIC in a xenograft model of human colon cancer. Because NIC has multiple biological activities, CP-NIC could be used for treatment of multiple diseases, including cancer, bacterial and viral infection, type II diabetes, NASH and NAFLD. Attachment of the hydrophobic drug NIC (purple triangles) to CP (black chains) triggers self-assembly into cylindrical nanoparticles.
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