Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy
Nanoparticle-mediated targeting of MAPK signaling predisposes tumor to chemotherapy
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DOI：
10.1073/pnas.0902857106
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发表时间：
2009-05-12
影响因子：
11.1
通讯作者：
Sengupta, Shiladitya
中科院分区：
文献类型：
--
作者：
Basu, Sudipta;Harfouche, Rania;Sengupta, Shiladitya
在大多数人类肿瘤中，MAPK信号转导级联反应失调。在这里，我们报告说，该途径的纳米颗粒介导的靶向可以优化癌症化疗。我们从独特的己酸酯，L-乳酸 - 乙醇酸聚合物化学结合到PD98059（一种选择性MAPK抑制剂）中设计了纳米颗粒。纳米颗粒通过癌细胞通过内吞作用吸收，并证明了活性剂的持续释放，从而抑制下游细胞外信号调节激酶的磷酸化。我们证明，纳米颗粒介导的MAPK靶向抑制了黑色素瘤和肺癌细胞的增殖，并在体外诱导凋亡。含黑色素瘤小鼠中PD98059-纳米颗粒的给药抑制了肿瘤的生长，并增强了顺铂化学疗法的抗肿瘤功效。我们的研究表明，纳米颗粒介导的信号转导抑制剂的传递可以作为癌症化学疗法的独特范例。
The MAPK signal transduction cascade is dysregulated in a majority of human tumors. Here we report that a nanoparticle-mediated targeting of this pathway can optimize cancer chemotherapy. We engineered nanoparticles from a unique hexadentate-polyD, L-lactic acid-co-glycolic acid polymer chemically conjugated to PD98059, a selective MAPK inhibitor. The nanoparticles are taken up by cancer cells through endocytosis and demonstrate sustained release of the active agent, resulting in the inhibition of phosphorylation of downstream extracellular signal regulated kinase. We demonstrate that nanoparticle-mediated targeting of MAPK inhibits the proliferation of melanoma and lung carcinoma cells and induces apoptosis in vitro. Administration of the PD98059-nanoparticles in melanoma-bearing mice inhibits tumor growth and enhances the antitumor efficacy of cisplatin chemotherapy. Our study shows the nanoparticle-mediated delivery of signal transduction inhibitors can emerge as a unique paradigm in cancer chemotherapy.