自脱落骨靶向MOFs载体递送saporin用于骨转移瘤治疗的研究

Protein drugs are one of the most promising new areas in drug research and development, however, great challenges are still faced in the drug delivery in vivo. Bone metastasis is one of the difficult points in cancer treatment. Previously, we constructed the targeted micelles for bone metastases. However，we found that although bone-targeting nanoparticles have good affinity for bone tissue, however, they are not easily to be desorbed from the surface of bone matrix, which further hinder the transport of nanoparticles from bone tissue to bone metastasis cells. In order to address these issues of protein delivery in vivo and the desorption of bone-targeting nanoparticles, we herein plan to construct and evaluate a bone-targeting nanoparticles, which possess the properties of self-dissociability from bone matrix for the treatment of cancer bone metastases by using MOFs, acid-sensitive targets (ALN-PEG-N=C-DSPE) and PEG-DSPE as materials and saporin, a kind of protein toxin, as cargoes. The nanocarrier are expected to accomplish the following five tasks of "bone targeting", "acid sensitive desorption",“lipid layer dissociation” "lysosome escape" and "ATP responsive drug release" successively, which might to realize the programmed and targeted delivery and release of protein drugs in bone metastases nidus. Altogether, this research project is expected to provide a new idea for the design of protein drug delivery systems for bone metastasis treatment.

蛋白质药物是药物研发中最有前景的新领域之一,但其体内递送仍面临诸多挑战。骨转移是肿瘤治疗的难点之一。申请人前期构建了针对骨转移瘤的治疗载体，但是发现这类载体虽然对骨组织具有较好的亲和力，但难以从骨基质表面脱附，阻碍了纳米粒从骨组织向附近肿瘤细胞的转运。为了解决蛋白质药物的体内递送问题，以及骨靶向纳米粒的脱附问题，本项目拟利用MOFs（金属有机框架）化合物、具有酸敏感性的靶头和PEG化磷脂等作为载体材料，以saporin蛋白（一种作用于核糖体的蛋白质毒素）作为载药，构筑一种具有自脱落靶头性质的骨靶向纳米粒，用于治疗骨转移瘤，并初步评价其机制。该载体可依次完成“骨靶向”、“酸敏脱附”、“脂质层解离”、“溶酶体逃逸”和“胞内ATP响应释药”等五项任务，以期解决上述两大问题，有望实现蛋白质药物在体内对骨转移瘤的程序化、靶向性递释。本项目希望为蛋白质药物递送以及骨转移瘤治疗载体的设计提供一种新思路。

项目负责人发展了一类新型的MOF结构包封的蛋白质药物和小分子药物用于肿瘤骨转移的递送载体，丰富了现有骨靶向药物递送系统。研究过程中发现了RANKL抗体与骨靶向载体的联合治疗作用，并利用这种效应设计了高效、低毒的新型抗肿瘤骨转移治疗方案。阐明了可脱落骨靶向载体的血清稳定性、酶敏感脱落性质、细胞摄入、内涵体逃逸、胞内酸敏感释放等多个步骤中的体外特征；并拓展了骨靶向载体用于骨关节炎等骨疾病治疗的应用研究，开展了该载体的体内外药效、药理机制评价，以及初步的药动学性质评价、生物相容性评价、蛋白质组学等机理研究工作。该项目完成期间，项目负责人以第一或通讯作者相继在ACS Nano，Advanced Functional Materials，Nanoscale，Journal of Materials Chemistry B等期刊上发表SCI研究论文6篇，并被Nature Protocols，Advanced Materials，Biomaterials等专业期刊所引用。申请发明专利2项，参加国际会议交流3次，培养研究生3名。在Journal of Controlled Release发表骨靶向载体综述"Targeting bone microenvironments for treatment and early detection of cancer bone metastatic niches"。这些研究工作为骨靶向载体的设计和骨转移瘤的治疗提供了新思路和理论支持。