Laboratory of Controllable Preparation and Application of Nanomaterials, CAS Key Laboratory of Cryogenics & State Key Laboratory of Technologies in Space Cryogenic Propellants, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, People's Republic of China.
Nanoscale. 2017 Jun 29;9(25):8834-8847. doi: 10.1039/c7nr02511d.
Combined thermo-chemotherapy displays outstanding synergically therapeutic efficiency when compared with standalone thermotherapy and chemotherapy. Herein, we developed a smart tri-stimuli-responsive drug delivery system involving X@BB-ZrO NPs (X represents loaded IL, DOX, keratin and tetradecanol) based on novel ball-in-ball-structured ZrO nanoparticles (BB-ZrO NPs). The microwave energy conversion efficiency of BB-ZrO NPs was 41.2% higher than that of traditional single-layer NPs due to the cooperative action of self-reflection and spatial confinement effect of the special two-layer hollow nanostructure. The tri-stimuli-responsive controlled release strategy indicate that integrated pH, redox and microwaves in single NPs based on keratin and tetradecanol could effectively enhance the specific controlled release of DOX. The release of DOX was only 8.1% in PBS with pH = 7.2 and GSH = 20 μM. However, the release could reach about 50% at the tumor site (pH = 5.5, GSH = 13 mM) under microwave ablation. The as-made X@BB-ZrO NPs exhibited perfect synergic therapy effect of chemotherapy and microwave ablation both in subcutaneous tumors (H22 tumor-bearing mice) and deep tumors (liver transplantation VX2 tumor-bearing rabbit model). There was no recurrence and death in the X@BB-ZrO + MW group during the therapy of subcutaneous tumors even on the 42 day. The growth rates in the deep tumor of the control, MW and X@BB-ZrO + MW groups were 290.1%, 14.1% and -42% 6 days after ablation, respectively. Dual-source CT was used to monitor the metabolism behavior of the as-made BB-ZrO NPs and traditional CT was utilized to monitor the tumor growth in rabbits. Frozen section examination and ICP results indicated the precise control of drug delivery and enhanced cytotoxicity by the tri-stimuli-responsive controlled release strategy. The ball-in-ball ZrO NPs with high microwave energy conversion efficiency were first developed for synergic microwave ablation and tri-stimuli-responsive chemotherapy, which may have potential applications in clinic.
联合热化疗与单独热疗和化疗相比具有显著的协同治疗效果。在此，我们开发了一种基于新型球中球结构氧化锆纳米粒子（BB-ZrO NPs）的智能三刺激响应药物递送系统，该系统涉及 X@BB-ZrO NPs（X 代表负载的 IL、DOX、角蛋白和十四醇）。由于特殊双层空心纳米结构的自反射和空间限制作用的协同作用，BB-ZrO NPs 的微波能量转换效率比传统的单层 NPs 高 41.2%。三刺激响应控制释放策略表明，基于角蛋白和十四醇的单个 NPs 中的集成 pH、氧化还原和微波可以有效地增强 DOX 的特异性控制释放。在 pH = 7.2 和 GSH = 20 μM 的 PBS 中，DOX 的释放仅为 8.1%。然而，在微波消融下肿瘤部位（pH = 5.5，GSH = 13 mM），释放量可达约 50%。所制备的 X@BB-ZrO NPs 在皮下肿瘤（H22 荷瘤小鼠）和深部肿瘤（肝移植 VX2 荷瘤兔模型）中均表现出化疗和微波消融的协同治疗作用。在治疗皮下肿瘤时，即使在第 42 天，X@BB-ZrO + MW 组也没有复发和死亡。消融后 6 天，对照组、MW 组和 X@BB-ZrO + MW 组深部肿瘤的增长率分别为 290.1%、14.1%和-42%。双源 CT 用于监测所制备的 BB-ZrO NPs 的代谢行为，传统 CT 用于监测兔的肿瘤生长。冷冻切片检查和 ICP 结果表明，三刺激响应控制释放策略可以精确控制药物递送并增强细胞毒性。具有高微波能量转换效率的球中球 ZrO NPs 首次用于协同微波消融和三刺激响应化疗，可能具有临床应用潜力。
