Department of Medicine, Laboratory of Nanomedicine, BWH-HST Center for Biomedical Engineering, Brigham and Women's Hospital, Harvard MedicalSchool, USA.
ACS Nano. 2010 Jan 26;4(1):574-82. doi: 10.1021/nn901465h.
Physically diverse carbon nanostructures are increasingly being studied for potential applications in cancer chemotherapy. However, limited knowledge exists on the effect of their shape in tuning the biological outcomes when used as nanovectors for drug delivery. In this study, we evaluated the effect of doxorubicin-conjugated single walled carbon nanotubes (CNT-Dox) and doxorubicin-conjugated spherical polyhydroxylated fullerenes or fullerenols (Ful-Dox) on angiogenesis. We report that CNTs exert a pro-angiogenic effect in vitro and in vivo. In contrast, the fullerenols or doxorubicin-conjugated fullerenols exerted a dramatically opposite antiangiogenic activity in zebrafish and murine tumor angiogenesis models. Dissecting the angiogenic phenotype into discrete cellular steps revealed that fullerenols inhibited endothelial cell proliferation, while CNTs attenuated the cytotoxic effect of doxorubicin on the endothelial cells. Interestingly, CNT promoted endothelial tubulogenesis, a late step during angiogenesis. Further, mechanistic studies revealed that CNTs, but not fullerenols, induced integrin clustering and activated focal adhesion kinase and downstream phosphoinositide-3-kinase (PI3K) signaling in endothelial cells, which can explain the distinct angiogenic outcomes. The results of the study highlight the function of physical parameters of nanoparticles in determining their activity in biological settings.
物理形态多样的碳纳米结构因其在癌症化疗方面的潜在应用而受到越来越多的研究。然而，当它们作为药物传递的纳米载体时，其形状对生物结果的影响的相关知识还很有限。在这项研究中，我们评估了载阿霉素的单壁碳纳米管（CNT-Dox）和载阿霉素的球形多羟基富勒烯或富勒醇（Ful-Dox）对血管生成的影响。我们报告 CNT 在体外和体内具有促血管生成作用。相比之下，富勒醇或载阿霉素的富勒醇在斑马鱼和鼠肿瘤血管生成模型中表现出显著相反的抗血管生成活性。将血管生成表型细分为离散的细胞步骤表明，富勒醇抑制内皮细胞增殖，而 CNT 则减弱了阿霉素对内皮细胞的细胞毒性作用。有趣的是，CNT 促进了内皮细胞小管形成，这是血管生成的晚期步骤。此外，机制研究表明，CNT 可诱导整合素聚集并激活粘着斑激酶和下游磷酸肌醇-3-激酶（PI3K）信号通路，而富勒醇则没有，这可以解释它们不同的血管生成结果。该研究结果强调了纳米粒子物理参数在决定其在生物环境中的活性方面的作用。
