远程调控介孔门控型磁性载体多机制治疗肿瘤研究

The co-transport system of Fe2+ donor and Fe2+-depentdent antitumor drug, with a remote-control function by alternating magnetic field (AMF), will be mainly investigated in this study. It employs new multifunctional hollow mesoporous magnetic nanoparticles (Hollow IONPs) as matrix (large surface area, high-capacity, low density, Fe2+ donor) and Fe2+-depentdent drug (artemisinin: ART) as a model drug, linkage of hyaluronic acid (HA) molecule via hydrazone bond, to achieve magnetic carrier of tumor targeting and controlled drug release. The features of the system are as follows: ①Heat and reactive oxygen species (ROS) can be generated under irradiation of AMF. ② It can achieve co-transport and positioning release of Fe2+ and Fe2+-depentdent drug. ③ Remote-control, positioning and combined modality therapy (hot, ROS and chemicals) for tumor will be realized. Herein, design and optimization of formulation will be carried out. The stability, encapsulation efficiency, drug loading, release profile, pH sensitivity of Fe2+ and heat and ROS response to AMF of the transport system will be also investigated. Thermal and ROS effect under AMF, biodistribution, pharmacokinetic parameters, will be investigated in breast tumor cells and tumor-bearing nude mice, to evaluate the comprehensive effects in vitro and in vivo.

构建具有交变磁场远程调控功能的Fe2+供体与Fe2+依赖性抗肿瘤药物共转运体系。以新型多功能中空介孔磁性纳米粒（Hollow IONPs）为基体(比表面积大，容量大，密度小，Fe2+供体)，Fe2+依赖性药物(以青蒿素代表: ART)为模型药, 通过腙键连接透明质酸（HA）分子，实现肿瘤靶向性和药物释放的门控作用。该体系在交变磁场照射下产热和活性氧（ROS），并实现Fe2+供体与Fe2+依赖性药物共转运、药物定位释放、同一位点多机制治疗肿瘤（热、活性氧和化学药物），达到远程定位调控肿瘤多机制治疗的目的。主要研究内容：HA-Hollow IONPs的制备、表征及载药处方设计和优化，考察其稳定性、包封率、载药量、释药特性、Fe2+的pH响应性及对交变磁场下热和ROS响应性；以乳腺癌细胞和荷瘤裸鼠为模型进行体内外研究，考察体系对交变磁场热和ROS效应，体内分布、药动学参数等，综合评价体内外效果。

本课题基于多功能纳米载体，主要构建了5种具有微能量及微环境响应功能的药物控释系统，克服脱靶效应，实现肿瘤多机制精准治疗。①以介孔Fe3O4纳米粒为基体，构建了一种交变磁场响应的Fe2+供体和Fe2+依赖性药物共转运递药系统HA-mFe3O4/ART。被肿瘤细胞摄取且定位于溶酶体后，同步释放Fe2+和ART。二者通过非酶促反应生成ROS，杀伤肿瘤细胞，联合交变磁场后，抗肿瘤效应可进一步提高3.9倍，从而实现肿瘤化疗-磁热—磁动力学一体化治疗。②.以CaP掺杂的中空介孔硫化铜为基体，构建了一个近红外激光响应的Ca2+ 纳米发生器，用于打破肿瘤细胞线粒体内Ca2+稳态，提高肿瘤光热治疗效果。③以叶酸修饰的中空介孔硫化铜纳米粒为基体，构建了一个具有近红外激光响应的相变型递药系统，实现了铜离子依赖的化疗-光疗协同治疗，为抗肿瘤治疗提供了新的策略。④以纳米Fe3O4作为肿瘤内源性抗原的载体，构建了核壳结构纳米药物递送系统，可实现个体化免疫治疗。⑤以纳米Fe3O4、亚油酸过氧化氢、膜融合脂质体等为材料，构建了一种连续的细胞内递送系统MFLs/LAOOH@DOX，用于乏氧肿瘤区域的深部渗透和肿瘤化疗-ROS多机制治疗，为提高基于ROS的抗肿瘤治疗效率提供了一种新的方法。本研究完成了项目计划书中所列的各项研究计划，在该领域发表SCI论文共16篇，其中一区文章14篇，二区文章2篇。授权国家发明专利17项。获得1项河南省科技进步一等奖。依托本项目资助，培养了4名博士生和6名硕士生，进站博士后3名。