School of Chemistry and Chemical Engineering, Harbin Institute of Technology, No.92, West Dazhi Street, Nangang District, Harbin 150001, China.
ACS Appl Mater Interfaces. 2020 Sep 30;12(39):43488-43500. doi: 10.1021/acsami.0c13164. Epub 2020 Sep 16.
Self-assembling natural small molecules (NSMs) with favorable anticancer activity are of increasing interest as novel drug delivery platforms without structural modification for biomedical applications. However, a lack of knowledge and practicability of NSMs as drug carriers limited their current biomedical application. Here, via a green and facile supramolecular coassembly strategy, we report and develop a series of carrier-free terpenoid natural small molecule-mediated coassembled photosensitive drugs for enhanced and synergistic chemo/photodynamic therapy. After screening 17 terpenoid NSMs, we identified 11 compounds that could form coassembled NSMs-Ce6 NPs with regulatable drug sizes. Analysis of the representative betulonic acid (BC)-mediated nano-coassemblies (BC-Ce6 NPs) reveals the high efficiency of the coassembly strategy and highlights the tremendous potential of NSMs as novel drug delivery platforms. Through molecular dynamics simulation and theoretical calculations, we elucidate the mystery of the coassembly process, indicating that the linear coplanar arrangement of BC dimeric units is primarily responsible for the formation of rod-like or spherical morphology. Meanwhile, we demonstrated that the reduced energy gap between the singlet and triplet excited states (Δ) facilitates efficient reactive oxygen species generation by promoting ·OH generation via a type I photoreaction mechanism. The assembled nanodrugs exhibit multiple favorable therapeutic features, ensuring a remarkably enhanced, synergistic, and secure combinatorial anticancer efficacy of 93.6% with highly efficient tumor ablation. This work not only expands the possibility of natural biodegradable materials for wide biological applications but also provides a new perspective for the construction of NSM-mediated nano-coassemblies for precision therapy.
具有良好抗癌活性的自组装天然小分子 (NSM) 作为新型药物递送平台，无需进行结构修饰即可用于生物医学应用，因此越来越受到关注。然而，由于对 NSM 作为药物载体的了解和实用性有限，限制了它们在当前生物医学中的应用。在这里，我们通过一种绿色简便的超分子共组装策略，报道并开发了一系列无载体萜类天然小分子介导的共组装光敏药物，以增强和协同化学/光动力治疗。在筛选了 17 种萜类 NSM 后，我们鉴定出 11 种能够形成具有可调节药物尺寸的共组装 NSM-Ce6 NPs 的化合物。代表性的桦木酸 (BC) 介导的纳米共组装体 (BC-Ce6 NPs) 的分析揭示了共组装策略的高效率，并突出了 NSM 作为新型药物递送平台的巨大潜力。通过分子动力学模拟和理论计算，我们阐明了共组装过程的奥秘，表明 BC 二聚体单元的线性共面排列主要负责形成棒状或球状形态。同时，我们证明了通过 I 型光反应机制促进 ·OH 生成，可使单重态和三重态激发态之间的能隙减小 (Δ)，从而有效地产生活性氧物种。组装后的纳米药物具有多种有利的治疗特性，确保了高达 93.6%的协同增强和安全的组合抗癌疗效，具有高效的肿瘤消融作用。这项工作不仅扩展了天然可生物降解材料在广泛的生物学应用中的可能性，还为 NSM 介导的纳米共组装用于精准治疗提供了新的视角。
