靶向肿瘤相关粘连蛋白EDB的超小纳米药物载体用于恶性脑瘤治疗

Blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) significantly limit the therapeutic effect of brain cancer treatment. Numerous researches have demonstrated that fibronectin extra domain B (EDB) is over-expressed on the membrane of brain tumor cells. Therefore, a new therapeutic strategy may be developed for brain tumor therapy by using EDB-targeting drug nanocarrier. The key scientific issue is to explore a targeting ligand showing specific recognition with EDB and develop a new nanocarrier that can efficiently overcome BBB and BBTB. We previously designed an EDB-targeting ligand, aptamer-like peptide (Aptide), which can specifically recognize EDB with high affinity. In addition, we also developed an ultra-small nanocarrier which can efficiently penetrate some dense blood vessels in tumor tissues. In our preliminary studies, we used the previously synthesized EDB-targeting ligand aptide to modify the ultra-small nanocarrier and the experimental results demonstrated that the aptide modification can enhance the ability of the resulting nanocarrier to overcome BBB and BBTB, leading to significant increase in the accumulation of the nanocarrier in the brain tumor tissues. Based on these encouraging experimental results, in this proposal, we will further prepare a series of aptide-modified ultra-small nanocarriers for targeted drug delivery. After systemically screening to obtain the optimal nanocarrier with the lowest toxicity but highest delivery efficiency, we will evaluate its efficacy for targeted brain tumor therapy by using xenograft and orthotopic tumor models. We expect that the research proposed here can provide scientific evidence and fundamental mechanism for the exploring new therapeutic strategy for brain tumor treatment.

血-脑屏障（BBB）和血-脑瘤屏障（BBTB）严重限制脑肿瘤治疗效果。大量研究表明，脑肿瘤细胞膜上粘连蛋白额外域B（EDB）表达量显著升高。使用靶向EDB的纳米药物载体有望成为一种新策略用于脑肿瘤治疗。其中关键的科学问题是找出EDB的高效靶向配体和设计出高效跨过BBB及BBTB的纳米载体。前期研究工作中，我们成功得到EDB的特异性靶向配体APTEDB。同时我们也开发出超小尺寸（~10 nm）的纳米载体，用于高效跨过肿瘤中结构致密性高的血管。预实验证实，APTEDB修饰超小纳米载体可增强其跨过BBB及BBTB的能力和靶向恶性脑瘤细胞的性能，显著提高纳米载体在恶性脑瘤中富集量。基于以上研究基础，本项目将进一步制备多个尺寸超小的EDB靶向纳米载体，筛选出低毒高效的纳米载体用于药物输送，在皮下移植瘤和原位移植瘤模型上考察其靶向治疗脑肿瘤的效果，为开发脑肿瘤新疗法提供科学依据和理论基础。

血-脑屏障（BBB）和血-脑瘤屏障（BBTB）严重限制脑肿瘤治疗效果。大量研究表明，脑肿瘤细胞膜上粘连蛋白额外域B（EDB）表达量显著升高。使用靶向EDB的纳米药物载体有望成为一种新策略用于脑肿瘤治疗。其中关键的科学问题是找出EDB的高效靶向配体和设计出高效跨过BBB及BBTB的纳米载体，用此载体设计出有效的抗肿瘤药物。. 前期研究工作中，我们成功得到EDB的特异性靶向配体APTEDB。同时我们也开发出超小尺寸（~10 nm）的纳米载体，用于高效跨过肿瘤中结构致密性高的血管。预实验证实，APTEDB修饰超小纳米载体可增强其跨过BBB及BBTB的能力和靶向恶性脑瘤细胞的性能，显著提高纳米载体在恶性脑瘤中富集量。基于以上研究基础，本项目将进一步制备多个尺寸超小的EDB靶向纳米载体，筛选出低毒高效的纳米载体用于药物输送，在皮下移植瘤和原位移植瘤模型上考察其靶向治疗脑肿瘤的效果，为开发脑肿瘤新疗法提供科学依据和理论基础。. 本项目研究工作进展顺利，按原计划完成了肿瘤靶向纳米粒子的体外性能测试，包括纳米粒子的药物包载效率、体外脑肿瘤细胞靶向内吞性能、体外细胞毒性检测、肿瘤细胞凋亡检测等，筛选出了低毒高效的纳米粒子；同时完成了纳米药物载体的体内性能测试，包括纳米载体的药代动力学特征、肿瘤靶向聚集能力、主要组织毒性检测、血清生化检测等，制备了高靶向性的抗肿瘤纳米药物。