基于抗癌药物高效发光和可视化联合用药的聚膦腈纳米送药系统

It has been a hotspot to develop a drug delivery system (DDS) with an imaging and targeting function for accurate cancer treatment and personalized therapy. Such a DDS can accurately monitor the drug delivery process and evaluate the treatment effects. This project proposed here is to design and prepare a serial of novel cross-linked polyphosphazene nanoparticles (PPZ NPs) with enhanced fluorescence, controllable biodegradation rate, and ability of loading other drugs for visualizing cancer treatment. The key fundamental issues and novelties include: 1）Enhanced fluorescence properties: the fluorescent anticancer drugs could be fixed in a cross-linked polyphosphazene nanoparticles as a reaction unit, which would effectively avoid the aggregation induced quenching and improve the photo-bleaching; 2) Regulating the degradation and release rate of drugs: the biodegradation rate and drug release rate could be controlled by introducing cystinate derivations and dipeptides to form copolymers; 3) improvement of treatment efficacy and reducing the drug resistance: Hollow PPZ NPs will be prepared by a Template Method and the size of nanopores on PPZ shells can be controlled by the diamine structures, the combined drugs could be therefore loaded to improve the treatment efficacy. This newly developed multifunctional nanosystem for drug delivery can provide novel insights into solving clinic challenges faced by accurate and personalized treatments.

为实现癌症的精准医疗和个性化治疗，开发具有靶向和成像功能的送药系统，精确示踪送药过程和评价治疗效果是目前研究的一个热点。本项目拟设计和制备一类具有增强荧光、生物降解速率可控、可同步联合用药和肿瘤靶向的交联聚膦腈纳米粒子用于肿瘤的可视化治疗。拟解决的关键科学问题和创新性包括：（1）增强荧光性能设计：将具有荧光性的抗肿瘤药物作为反应单元固定在生物相容的交联聚膦腈纳米粒子中，能有效解决聚集引起的荧光淬灭并提高耐光漂白性；（2）药物降解释放速率调控：引入胱氨酸二甲酯或二肽等易降解的二胺化合物共聚调控生物降解速率和药物释放速度；（3）提高疗效和降低耐药性：模板法实现中空纳米粒子的制备和中空结构调控，通过改变二氨分子结构调控交联聚膦腈纳米壳的微孔尺寸，进而负载顺铂等药物进行联合用药。本项目针对精准治疗和个性化医疗设计的新型的多功能性纳米送药体系将为解决临床难题提供新的思路。

为实现癌症的精准医疗和个性化治疗，开发具有靶向和成像功能的送药系统，精确示踪送药过程和评价治疗效果是目前研究的一个热点。本项目充分利用载体材料和抗癌药物的多功能性来简化用于多模诊疗的纳米药物的结构和制备工艺，并通过合理结构设计发挥载体和药物间的协同效应以实现高性能和多功能。因此，设计和制备了一系列生物降解速率可调、高载药率和药物可控释放的药物功能化交联聚磷腈纳米粒子，通过引入pH或GSH响应单元可有效调控其生物降解速率和药物释放速率，载药率最高可达85.64%，肿瘤微环境低pH和高GSH浓度的条件下（pH5.5+20 mM GSH）48小时释放效率最高可达83%，并在细胞和荷瘤裸鼠模型上对肿瘤具有优异的抑制效率而对正常器官无损伤，其在抗肿瘤小分子药物刺激响应释放和长效缓释方面具有极大的应用前景；利用药物功能化聚磷腈和无机纳米材料复合，成功构建了聚磷腈基纳米诊疗试剂将其用于肿瘤多模诊疗，通过超顺磁四氧化三铁纳米粒子和二氧化锰纳米片分别提供MRI成像功能以及化学动力学治疗效果，通过Ce6或亚甲基蓝提供光动力治疗功能，通过交联聚磷腈实现化疗药物的可控释放，最终在细胞和荷瘤裸鼠水平上实现了对肿瘤的高效治疗和活体成像效果；通过无模板法实现了yolk-shell型交联聚磷腈纳米反应器的一步法制备，其对TMB和ABTS具有优异的循环稳定性；通过控制反应参数调控聚磷腈交联度首次获得了药物功能化超支化聚磷腈材料，可将药物功能化聚磷腈的降解速率和药物释放速率进一步提高；还将天然提取物功能化聚磷腈用于商业化物理防晒剂的改性，聚磷腈包覆层可通过吸收和散射有效降低无机纳米粒子产生ROS的效率，聚磷腈中固定的白藜芦醇和进一步淬灭无机纳米粒子产生的ROS，同时聚磷腈包覆层有效增大其粒径，降低了无机纳米粒子进入体内富集造成的潜在威胁，获得了具有优异紫外吸收和散射、极高生理安全性的复合防晒剂材料。