基于模块组合技术构建多功能关联的纳米硒/铁/硅基药物载体研究

The extensive side effect and typical drug resistance in chemotherapy challenged the clinic in tumor therapy. To date, the combinational targeting for high targeting efficiency, the controlled release in targeted site co-triggered with different factors and enhanced synergistic effect in favor of two-drug combination mostly attracted interests. Though they achieved some, it would be better to constitute a drug delivery system combining all the features above. Expected, the novel system will perform more efficiency. On the other hand, it is intricate to integrate all these features into one nano-device in light of the convenient approaches. Herein, a modular combinational strategy (MCS) was proposed for the achievement of these purposes. Building blocks, comprising of folate receptor and superparamagnetic iron oxide nanoparticle (SPION) for targeting, comprising of pH/reduction responsiveness for synergistically controlled release, comprising of nanosized selenium for synergistic effect, and comprising of mesoporous silica nanoparticels for drug loading, were prepared ahead. The ready prepared building blocks were then integrated into a nano device in favor of the MCS. The device will provide a combinational functions for achievement of the low side effect and high therapy efficacy in chemotherapy. The principal contribution lies in the idea of MCS and the integration of all these features which were investigated individually elsewhere.

临床应用的化疗药物依然存在毒副作用大、易产生耐药等缺点，提高治疗效果、降低毒副作用是当前急需解决的重要问题。目前，采用联合靶向提高靶向效率、多参数共同控制药物在靶区选择性释放以及联合用药实现协同增效等措施，分别起到了一定效果。显然，将上述思想整合到一个药物传递系统，对提高治疗效果、降低毒副作用具有重要意义。此外，将不同功能整合到一个纳米系统中，通常涉及较复杂的制备与合成过程。本项目提出功能模块组合技术，制备多功能关联的药物载体。先分别合成四氧化三铁纳米粒子靶向模块、pH/还原响应的级联控释模块、基于纳米硒的协同增效模块、基于介孔纳米二氧化硅的载药模块，再通过组合技术一步将功能模块整合在同一载体中。采用细胞学及动物模型研究。主要成果体现在提出了模块组合技术，并采用该技术制备复杂功能关联的载药体系。该研究将为构建复杂功能纳米材料提供新思路，为开拓多功能关联的高效肿瘤治疗剂提供新方法。

圆满解决了课题当初提出的关键科学问题，取得了项目预期的成果，实现了项目的创新性思想。在联合靶向、级联控制释放、协同增效等方面对功能模块进行优化，通过模块间的简单组合，成功构建高效靶向、定点释放、毒性降低等复杂功能相互关联的药物输送系统，已全面完成了预期的考核指标。成功获得联合靶向、级联控制释放、协同增效为一体的药物载体，为抗肿瘤治疗纳米技术提供一种新的制备平台。在此基础上，还进行了部分工作的拓展，具体体现在：.①首次提出了利用通过Se-S键调控还原降解速率的设计，获得降解速率可调的药物载体，对药物在还原性环境中的释放速率进行调节。.②获得具有逻辑“与”结构关联的双因素协同控制释放机制的纳米药物载体，通过pH和还原响应的双重联动控制，实现降低毒副作用的目的；通过磁靶向实现靶区的定向协同效果。.③通过酸敏感化学结构将载体与化疗药物进行化学键链接，实现药物在正常组织的释放锁闭，进一步达到降低毒副作用，提高疗效的目的。.④通过酸诱导电荷反转机制，获得pH/还原双响应磁靶向纳米载体，通过组合型设计，严格限制了药物在正常组织环境中的过早释放，达到提高肿瘤区域药物浓度，提高靶向治疗效果的目的。.⑤利用纳米硒粒子协同DOX抗肿瘤能力，纳米硒的引入一方面协同提高了药物系统的抗癌能力，另一方面降低DOX用量的目的，有效降低毒副作用。.⑥通过化疗与光热、光动力治疗联合机制的设计，达到协同增效的目的，有效提高治疗效果。. ⑦通过光热、光动力治疗与超顺磁纳米粒子的复合，联合与诊疗机制的设计，达到实现诊疗一体化的目的。.此外，加强了对外交流，与香港浸会大学和福建医科大学孟超肝胆研究院合作，开展了化疗、光热治疗、光动力治疗等多因素协同纳米载药平台在肿瘤诊断和治疗中的应用研究。