Fan Feng, Piao Ji-Gang, Zhao Yangyang, Jin Lijun, Li Mingyang, Wang Yucai, Yang Lihua
ACS Appl Bio Mater. 2020 Feb 17;3(2):1267-1275. doi: 10.1021/acsabm.9b01143. Epub 2020 Jan 21.
Membrane-disruptive, drug-free macromolecular therapeutics may help overcome cancer drug-resistance. Their inability to distinguish cancerous from normal cells, however, results in significant off-target toxicity. Note that the tumor has a slightly acidic microenvironment (pH 6.5-6.8) in contrast to the alkaline microenvironment in normal tissues (pH 7.4) and that host-defense peptides (HDPs) and their synthetic mimetics need to be net cationic to be membrane-disruptive. We herein endow polymer mimetics of HDPs with acid-triggered cationicity, to make them membrane-disruptive at only tumor pH. For these polymer mimetics, there exists a maximal threshold of chain length that determines whether the micelle of a mimetic inherits its pH-sensitive activity. Using the most and least active micelles as representatives, we find that their distinct potency in disrupting membranes arises because of their striking tendency to dissociate upon exposure to tumor pH. As expected, these micelles exhibit in vitro cytotoxicity profiles that correlate with their membrane-disruptive activity profiles. When administered intravenously, these micelles-irrespective of their distinct activity profiles-unanimously exhibit long systemic circulation as do PEGylated micelle nanoparticles, despite of their lacking stealth materials, owing to the zwitterionic nature of their surfaces at blood pH. Nevertheless, the pH-sensitive micelle achieves significantly higher tumor uptake and strikingly better therapeutic efficacy than its completely inactive analogue. More important, the pH-sensitive micelle exhibits undetectable off-target toxicity, owing to its pH-sensitivity. Clearly, making HDPs and their mimetics sensitive to tumor-characteristic cues (e.g., acidic pH) is efficient in minimizing their off-target toxicity, thereby offering membrane-disruptive, drug-free macromolecular therapeutics for fighting against cancer drug-resistance.
具有膜破坏作用的无药大分子疗法可能有助于克服癌症耐药性。然而，它们无法区分癌细胞和正常细胞，导致显著的脱靶毒性。值得注意的是，肿瘤具有微酸性微环境（pH 6.5 - 6.8），而正常组织为碱性微环境（pH 7.4），宿主防御肽（HDPs）及其合成模拟物需要呈净阳离子性才能具有膜破坏作用。我们在此赋予HDPs的聚合物模拟物酸触发的阳离子性，使其仅在肿瘤pH值下具有膜破坏作用。对于这些聚合物模拟物，存在一个最大链长阈值，该阈值决定了模拟物的胶束是否继承其pH敏感活性。以活性最高和最低的胶束为代表，我们发现它们在破坏膜方面的不同效力源于它们在暴露于肿瘤pH值时显著的解离倾向。正如预期的那样，这些胶束表现出与它们的膜破坏活性谱相关的体外细胞毒性谱。静脉给药时，尽管缺乏隐身材料，但由于其在血液pH值下表面的两性离子性质，这些胶束——无论其不同的活性谱如何——都与聚乙二醇化胶束纳米颗粒一样一致地表现出长循环时间。然而，pH敏感胶束比其完全无活性的类似物实现了显著更高的肿瘤摄取和明显更好的治疗效果。更重要的是，由于其pH敏感性，pH敏感胶束表现出不可检测的脱靶毒性。显然，使HDPs及其模拟物对肿瘤特征线索（如酸性pH）敏感可有效降低其脱靶毒性，从而为对抗癌症耐药性提供具有膜破坏作用的无药大分子疗法。
