基于血液组分白蛋白和红细胞构建的仿生靶向纳米粒用于肿瘤的协同治疗

It remains a critical challenge to design functional anti-tumor drug delivery systems (DDS) with good safety for clinical use. With long-term evolution, natural substances in life body are highly optimized for their specific functions in vivo and possess features that are often desired in DDS. Importantly, their merits of non-toxicity, non-immunogenicity, biodegradability and biocompatibility meet the requirements for safe DDS. Inspired by their naturally excellent functions, here biomimetic targeted nanoparticles (BNPs) were constructed based on albumin and red blood cells (RBC) derived from the blood of patient. Redox-responsive albumin nanoparticles containing antitumor drug was firstly prepared by crossing-linking agent glutathione, and then RBC membrane were coated onto nanoparticles for enhanced circulation in vivo. Tumor Necrosis Factor-Related Apotosis-inducing Ligand (TRAIL) was finally adsorbed on the surface of RBCM for tumor-targeted delivery. After administration back to patient’s blood vessels, it is expected that BNPs would display longer circulation time, good permeation through vascular wall base on enhanced permeability and retention effect, improved targeting ability through TRAIL-mediated drug delivery, and better synergistic anti-tumor efficacy by both TRAIL-induced apoptosis and drug-induced killing. In conclusion, BNPs may show promising potential in clinical use as functional carriers with good safety for synergistic and effective anti-tumor therapy.

抗肿瘤药物递送载体兼顾安全性和功能性一直是亟待解决的关键科学问题。生命体内的自然生物成分经过长期的发展和进化，具有了药物递送载体所需的某些特定功能，且本身安全无毒、无免疫原性、生物可降解且相容性好。基于一种“源于自然，归于自然”的设计理念，本项目在充分注重药物载体安全性的前提下，采用患者血液的组成成分白蛋白和红细胞（RBC）构建仿生靶向纳米粒（源于自然）。首先制备功能性载抗肿瘤药物的白蛋白纳米粒（二硫键交联），并在粒子的外表面包裹RBC膜，发挥RBC膜与生俱来的长循环功能，然后在RBC膜表面修饰肿瘤坏死因子相关凋亡诱导配体(TRAIL)，用于靶向肿瘤细胞并兼具诱导肿瘤细胞凋亡功能。最后将纳米粒重新注回患者血液内（归于自然），期待纳米粒有效靶向肿瘤细胞并在细胞内氧化-还原敏感型释放载药（二硫键断裂），发挥靶向协同治疗肿瘤作用及提高对肿瘤的治疗效率，实现抗肿瘤药物的功能性递送与安全递送。

抗肿瘤药物递送载体兼顾安全性和高效性一直是亟待解决的关键科学问题。开发本身绿色安全、生物相容性好，克服治疗中存在的多药耐药问题的纳米药物载体是本项目的研究重点。本项目采用一种简单和绿色的联合光敏剂二氢卟吩e6（Ce6）和化疗药物阿霉素（Dox）的自组装方法制备了一种含有光敏剂和化疗药物的高效低毒纳米载体。该自组装纳米粒子具有高载药率，通过改变Ce6/Dox比例，纳米粒尺寸可实现从纳米到微米尺度的调控。进一步的体内评价中，该纳米粒可实现纳米药物在活体动物体内的荧光示踪及肿瘤成像，活体成像结果显示出明显的EPR效果，实现了纳米粒在肿瘤部位选择性富集。光敏剂产生的光动力效应克服了化疗药物Dox的多药耐药性，而Dox对深层肿瘤细胞的有效杀伤弥补光动力疗法在组织穿透方面局限。两者结合达到了协同治疗肿瘤作用及提高对肿瘤的治疗效率，实现抗肿瘤药物的功能性递送与安全递送。项目研究目前已申报国家发明专利2项，发表SCI学术论文7篇，培养硕士研究生2名。