Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Suzhou, 215123, China.
Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Suzhou, 215123, China.
Biomaterials. 2019 Dec;223:119463. doi: 10.1016/j.biomaterials.2019.119463. Epub 2019 Aug 30.
The success of photothermal therapy (PTT) is often hampered by the thermo-resistance of tumor cells mediated by over-expressed heat shock proteins (HSPs). Herein, we developed a guanidine-rich, spherical helical polypeptide (DPP) with multivalency-assisted strong membrane penetrating capability, which mediated effective RNAi against tumor glycolysis metabolism to sensitize PTT. ICG was loaded into the internal cavity of DPP, and siRNA against pyruvate kinase M2 (siPKM2) was condensed by DPP to form positively charged nanocomplexes (NCs). The NCs were further coated with human serum albumin to enhance serum stability, prolong blood circulation, and improve tumor targeting. Due to its multivalent topology, DPP exhibited stronger membrane activity yet lower cytotoxicity than its linear analogue (LPP), thus enabling efficient PKM2 silencing in MCF-7 cells in vitro (75%) and in vivo (70%). The PKM2 silencing inhibited tumor glycolysis metabolism and further depleted the energy supply for HSPs production, thus overcoming the heat endurance of tumor cells to strengthen ICG-mediated photothermal ablation. Additionally, siPKM2-mediated energy depletion led to tumor cell starvation, which imparted synergistic anti-cancer effect with PTT. This study therefore provides a promising strategy for designing membrane-penetrating siRNA delivery materials, and it renders a unique RNAi-mediated anti-metabolic mechanism in sensitizing PTT and enabling starvation therapy.
光热疗法（PTT）的成功往往受到肿瘤细胞热抗性的阻碍，这种热抗性是由过度表达的热休克蛋白（HSPs）介导的。在此，我们开发了一种胍基丰富的、具有多价辅助强膜穿透能力的球形螺旋多肽（DPP），它介导有效的 RNAi 来抑制肿瘤糖酵解代谢，从而增强 PTT 的效果。ICG 被装载到 DPP 的内腔中，siRNA 针对丙酮酸激酶 M2（siPKM2）被 DPP 浓缩形成带正电荷的纳米复合物（NCs）。NCs 进一步用人血清白蛋白（HSA）包覆以增强血清稳定性、延长血液循环时间并提高肿瘤靶向性。由于其多价拓扑结构，DPP 表现出比其线性类似物（LPP）更强的膜活性和更低的细胞毒性，因此能够有效地在 MCF-7 细胞中进行 PKM2 沉默（体外约 75%，体内约 70%）。PKM2 沉默抑制了肿瘤糖酵解代谢，并进一步耗尽了 HSPs 产生所需的能量供应，从而克服了肿瘤细胞的耐热性，增强了 ICG 介导的光热消融效果。此外，siPKM2 介导的能量耗竭导致肿瘤细胞饥饿，与 PTT 产生协同抗癌作用。因此，本研究为设计穿透细胞膜的 siRNA 递送材料提供了一种有前途的策略，并为增强 PTT 和实现饥饿治疗提供了一种独特的 RNAi 介导的代谢抑制机制。
