超声响应性纳米Pickering乳剂用于耐药肿瘤协同治疗的研究

It is a major challenge to achieve highly efficient antitumor therapy in drug resistant cancer treatment. Drug nanocarriers with synergistic antitumor capabilities are considered as a promising strategy to improve therapeutic efficacy of drug resistant tumor. In this application, we propose to develop novel ultrasound responsive nanoscale Pickering emulsions based on cisplatin-loaded human serum albumin (HSA) nanoparticles (Pt@HSA) and Cypate-loaded HSA nanoparticles (Cy@HSA) to encapsulate phase-change liquid perfluorocarbon (PFC) for synergistic chemo-photothermal antitumor therapy. Ultrasound irradiation can trigger the liquid-gas phase change of PFC to form microbubbles, leading to direct and efficient cytoplasm co-delivery of Pt@HSA and Cy@HSA nanoparticles via sonoporation. Pt@HSA in the cytoplasm can directly release cisplatin to enter nuclei for significantly improved chemotherapeutic efficacy. Photothermal effect of Cypate upon near infrared laser irradiation could not only directly induce tumor cell necrosis for efficient photothermal therapy (PTT), but also result in the inhibition on the expression of multidrug resistance-associated protein 1 (MRP1) to reduce the efflux for further enhanced efficacy. Therefore, highly efficient antitumor efficacy could be achieved through synergistic chemo-photothermal therapy facilitated by ultrasound responsive cytoplasm delivery and multiple functionalities of photothermal effect. The application will elucidate the key role of nanoscale Pickering emulsions based on phase-change PFC in ultrasound responsive drug delivery, and the mechanism of synergistic therapeutic effect between PTT and chemotherapy. This work has great potential to provide theoretical and practical basis for the development of efficient antitumor therapeutic strategy by exploring novel stimuli responsive drug nanocarriers, and will be highly valuable in anticancer research and application.

耐药肿瘤的高效治疗是癌症治疗领域面临的重大挑战，构建新型纳米药物载体实现协同治疗，是提高治疗效果的有效手段。本项目拟采用载顺铂和载碳菁染料的白蛋白纳米粒，包裹相变型液态氟碳化合物，构建新型超声响应性纳米Pickering乳剂，用于耐药肿瘤的光热/化疗协同治疗。通过声致相变和声孔效应，可实现两种纳米粒在胞浆内直接、高效的共递送。胞浆内顺铂纳米粒可直接释药进入细胞核，有效增强化疗效果；同时碳菁染料在近红外光照下的光热效应，不仅能直接诱导肿瘤细胞急性坏死，还可抑制多药耐药相关蛋白的表达，降低药物外排，显著逆转肿瘤耐药性。结合超声响应释药和光热效应引起的多重作用，有望通过光热/化疗的协同增效，实现耐药肿瘤高效治疗。本项目通过阐明相变型纳米Pickering乳剂在超声响应性药物递送中的关键作用，明确光热治疗与化疗的协同作用机制，有望探索新型响应性纳米药物载体，具有较大的理论研究意义及潜在应用价值。

肿瘤的高效治疗是癌症治疗领域面临的重大挑战，构建新型纳米药物载体实现协同治疗，是提高治疗效果的有效手段。本项目首先构建了基于白蛋白模板法的多功能诊疗纳米粒，用于多模态影像指导下的肿瘤协同治疗；其次，采用混合的白蛋白纳米粒包裹相变型液态氟碳化合物，发展了超声响应性纳米Pickering乳剂，不仅可通过气液相变实现超声响应释药，还可有效提升纳米Pickering乳剂的纵向弛豫率，从而实现高信噪比的肿瘤磁共振造影成像，并对原位乳腺癌及其肺转移均有显著抑制效果；此外，我们还构建了肿瘤微环境响应型一氧化碳纳米前药，利用肿瘤细胞内较高的过氧化氢水平，实现一氧化碳的定点释放，实现了乳腺肿瘤的高效治疗。在本项目的资助下，项目负责人作为通讯作者在Angew Chem Int Ed、Small、Acta Biomater等高水平国际期刊发表SCI论文5篇，其中影响因子大于10的论文3篇，获得授权中国发明专利2项。