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Cholesterol-directed nanoparticle assemblies based on single amino acid peptide mutations activate cellular uptake and decrease tumor volume
Chemical Science ( IF 7.6 ) Pub Date : 2017-09-11 00:00:00 , DOI: 10.1039/c7sc02616a Shang Li 1, 2, 3, 4, 5 , Rongfeng Zou 1, 2, 3, 4, 5 , Yaoquan Tu 6, 7, 8, 9, 10 , Junchen Wu 1, 2, 3, 4, 5 , Markita P. Landry 11, 12, 13, 14, 15
Chemical Science ( IF 7.6 ) Pub Date : 2017-09-11 00:00:00 , DOI: 10.1039/c7sc02616a Shang Li 1, 2, 3, 4, 5 , Rongfeng Zou 1, 2, 3, 4, 5 , Yaoquan Tu 6, 7, 8, 9, 10 , Junchen Wu 1, 2, 3, 4, 5 , Markita P. Landry 11, 12, 13, 14, 15
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Peptide drugs have been difficult to translate into effective therapies due to their low in vivo stability. Here, we report a strategy to develop peptide-based therapeutic nanoparticles by screening a peptide library differing by single-site amino acid mutations of lysine-modified cholesterol. Certain cholesterol-modified peptides are found to promote and stabilize peptide α-helix formation, resulting in selectively cell-permeable peptides. One cholesterol-modified peptide self-assembles into stable nanoparticles with considerable α-helix propensity stabilized by intermolecular van der Waals interactions between inter-peptide cholesterol molecules, and shows 68.3% stability after incubation with serum for 16 h. The nanoparticles in turn interact with cell membrane cholesterols that are disproportionately present in cancer cell membranes, inducing lipid raft-mediated endocytosis and cancer cell death. Our results introduce a strategy to identify peptide nanoparticles that can effectively reduce tumor volumes when administered to in in vivo mice models. Our results also provide a simple platform for developing peptide-based anticancer drugs.
中文翻译：
基于单个氨基酸肽突变的胆固醇定向纳米颗粒组装体可激活细胞摄取并减少肿瘤体积
肽类药物由于体内活性低而难以转化为有效的疗法稳定。在这里，我们报告了通过筛选由赖氨酸修饰的胆固醇的单点氨基酸突变而不同的肽库来开发基于肽的治疗性纳米颗粒的策略。发现某些胆固醇修饰的肽促进和稳定肽α-螺旋的形成，从而产生选择性的细胞可渗透的肽。一种胆固醇修饰的肽通过肽间胆固醇分子之间的分子间范德华相互作用而稳定地组装成具有相当大的α-螺旋倾向的稳定的纳米颗粒，并且在与血清孵育16小时后显示出68.3％的稳定性。纳米粒子继而与癌细胞膜中不成比例的细胞膜胆固醇相互作用，从而诱导脂质筏介导的内吞作用和癌细胞死亡。体内小鼠模型。我们的结果也为开发基于肽的抗癌药物提供了一个简单的平台。
更新日期：2017-09-22
中文翻译：
基于单个氨基酸肽突变的胆固醇定向纳米颗粒组装体可激活细胞摄取并减少肿瘤体积
肽类药物由于体内活性低而难以转化为有效的疗法稳定。在这里，我们报告了通过筛选由赖氨酸修饰的胆固醇的单点氨基酸突变而不同的肽库来开发基于肽的治疗性纳米颗粒的策略。发现某些胆固醇修饰的肽促进和稳定肽α-螺旋的形成，从而产生选择性的细胞可渗透的肽。一种胆固醇修饰的肽通过肽间胆固醇分子之间的分子间范德华相互作用而稳定地组装成具有相当大的α-螺旋倾向的稳定的纳米颗粒，并且在与血清孵育16小时后显示出68.3％的稳定性。纳米粒子继而与癌细胞膜中不成比例的细胞膜胆固醇相互作用，从而诱导脂质筏介导的内吞作用和癌细胞死亡。体内小鼠模型。我们的结果也为开发基于肽的抗癌药物提供了一个简单的平台。
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