PFH脂质体用于改善缺氧治疗抗性和超声成像的研究

The occurrence of malignant tumors is a complicated process due to various internal and external factors. Sole-therapy development has been limited by compensatory increase of carcinogenic factors when a single factor is suppressed. In addition, the hypoxia microenvironment is also a major reason that causes therapy resistance. In this study, an O2 supplementary delivery system loaded with photo-/chemo-therapy drugs has been designed to overcome above hindrances. An ultrasound/fluorescence dual imaging model has been designed to monitor therapeutics, furthermore, a “Small-to-Large” method has been introduced to achieve expected sizes during circulation and imaging. Based on the above conditions, perfluorohexane, which is selected as O2 supplementary and ultrasound contrast agent, is encapsulated in liposomes with multi-therapeutic agents, Ce6 and PTX. After accumulating in tumor sites, the nanocarriers perform responsive agents release and consequently reassemble into micron ultrasound contrast agent. This multifunctional theranostic system provides new references for solution of O2-dependent therapy resistance and size-limited ultrasound imaging.

恶性肿瘤的发生和发展是体内外多因素相互作用的复杂过程，现有的多重治疗手段虽能有效避免单一靶点抑制造成的致病因素代偿性增加等问题，但是药物的低靶向效率和肿瘤缺氧微环境仍极大地限制了治疗效果。本课题设计O2输送载体，将O2与光疗/化疗药物共同递送至肿瘤, 通过超声诱导的O2气泡生成效应实现响应性释药,同时解决缺氧造成的治疗抗性。为了在治疗的同时实现体内示踪，采用超声/荧光双模态成像体系，并设计“Small-to-Large”粒径生长载体以解决长期困扰超声造影剂的粒径问题。同时考虑以上治疗/成像目的，本项目选用全氟己烷作为供氧剂和超声造影剂，在肿瘤部位响应性释放O2和药物，同时重组为有优良超声成像性能的微米级粒子，实现光疗/化疗双重疗法和超声/荧光双模态成像目的。该体系为改善肿瘤缺氧微环境提供了思路，对解决O2依赖治疗抗性有一定指导意义，同时对不同体内示踪方案，尤其是超声成像提供了一定参考价值。

肿瘤乏氧微环境不仅与肿瘤快速增殖、转移、血管增生等密切相关，而且会大大地削弱O2依赖抗肿瘤治疗的效果，例如光动力治疗和放疗等。本项目针对肿瘤乏氧微环境造成的治疗抗性，深入揭示肿瘤微环境复杂性与其造成治疗抗性的机理，寻求高效、低毒的克服治疗抗性的途径，同时借助智能响应药物递送体系的设计，提高靶位药物的治疗浓度并力求实现瘤内精准输药。本项目旨在开发氧气输送与光动力治疗相结合的多靶点治疗体系，设计可携氧的多功能药物输送脂质体，实现高效的肿瘤治疗及影像诊断，研究内容包括以下方面：1）将临床血液代用品全氟己烷作为氧气溶剂制备脂质体，提高肿瘤部位氧气输送效率，缓解乏氧并提高氧气依赖治疗手段的疗效；2）通过内外源刺激结合的手段，实现载体的可控释药；3）借助脂质体粒径可变的优势，和氟化碳材料在超声刺激下发生响应性液-气转变的特性，实现响应性超声成像的目的。