Acidity-Triggered Tumor Retention/Internalization of Chimeric Peptide for Enhanced Photodynamic Therapy and Real-Time Monitoring of Therapeutic Effects
Acidity-Triggered Tumor Retention/Internalization of Chimeric Peptide for Enhanced Photodynamic Therapy and Real-Time Monitoring of Therapeutic Effects
复制标题
酸度触发嵌合肽的肿瘤保留/内化，用于增强光动力治疗和治疗效果的实时监测
DOI：
10.1021/acsami.7b04447
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发表时间：
2017-05-17
影响因子：
9.5
通讯作者：
Han, He -You
中科院分区：
文献类型：
--
作者：
Han, Kai;Zhang, Wei-Yun;Han, He -You
光动力学疗法（PDT）在肿瘤治疗中具有巨大的前景。然而，仍然非常期望开发具有改善的肿瘤积累/内化和及时的治疗反馈的易于制造的PDT系统。在这里，我们报告了一个肿瘤酸度响应嵌合肽增强PDT和非侵入性实时凋亡成像。体外和体内研究均表明，肿瘤微环境中的弱酸性可以触发嵌合肽中羧酸根阴离子的快速质子化，这导致嵌合肽的疏水性增加，疏水性改善，尺寸扩大受控，以及从球形到球柱体形状的精确形态转换。所有这些因子实现了在肿瘤区域的超快速积累和延长滞留，选择性细胞内化，以及增强PDT对肿瘤的作用。同时，该嵌合肽在光动力治疗过程中可进一步产生活性氧，启动细胞凋亡。随后形成的caspase-3酶水解嵌合肽，实现了高信噪比和及时的荧光反馈。重要的是，直接利用生物功能Asp-Glu-Val-Asp-Gly（DEVDG，半胱天冬酶-3酶底物）肽序列的酸性响应性显著简化了制备并最大程度地提高了嵌合肽的性能。
Photodynamic therapy (PDT) holds great promise in tumor treatment. Nevertheless, it remains highly desirable to develop easy-to-fabricated PDT systems with improved tumor accumulation/internalization and timely therapeutic feedback. Here, we report a tumor-acidity-responsive chimeric peptide for enhanced PDT and noninvasive real-time apoptosis imaging. Both in vitro and in vivo studies revealed that a tumor mildly acidic microenvironment could trigger rapid protonation of carboxylate anions in chimeric peptide, which led to increased ζ potential, improved hydrophobicity, controlled size enlargement, and precise morphology switching from sphere to spherocylinder shape of the chimeric peptide. All of these factors realized superfast accumulation and prolonged retention in the tumor region, selective cellular internalization, and enhanced PDT against the tumor. Meanwhile, this chimeric peptide could further generate reactive oxygen species and initiate cell apoptosis during PDT. The subsequent formation of caspase-3 enzyme hydrolyzed the chimeric peptide, achieving a high signal/noise ratio and timely fluorescence feedback. Importantly, direct utilization of the acidity responsiveness of a biofunctional Asp–Glu–Val–Asp–Gly (DEVDG, caspase-3 enzyme substrate) peptide sequence dramatically simplified the preparation and increased the performance of the chimeric peptide furthest.