膜抗原PRAME引导的化疗联合靶向GSK3β/NFκB新型磁性多功能纳米颗粒的构建及抗骨肉瘤作用的研究

Resistance to chemotherapy and side effects are the key reasons of the treatment failure of osteosarcoma. Nanoparticle drug delivery system is a promising technology to enhance drug efficacy and reduce its side effects through targeted and delayed/controlled drug release. However, the targeted, efficient and secure multi-functional nano-medicine delivery system in the treatment of osteosarcoma can be hardly achieved. Our research found that ①The preferentially expressed antigen of melanoma(PRAME) is a potential therapeutic marker for its specific expression on osteosarcoma cell membrane; ②Glycogen synthase kinase-3β (GSK-3β) is an attractive therapeutic target for its regulation of the growth of osteosarcoma cells through modulating the activity of NF-κB pathway. ③Degradable magnetic microcapsule with multicompartment structure can be prepared by multiple fluid jet technology. In this project, we are going to encapsule chemotherapy drugs and GSK-3β/NF-κB inhibitor independently into PRAME targeted microcapsules, then to evaluate it by means of stability and magnetic measurements, drug loading and drug release study and antibody activity identification method,etc. Finally, we are going to assess targeting and anti-osteosarcoma effects of our drug delivery system both in vitro and in vivo through a variety of cell and animal models. The project will provide new therapeutic direction and strategies for osteosarcoma.

化疗药物耐药及其毒副作用是骨肉瘤临床治疗的瓶颈，亟需新的治疗策略。纳米给药系统可通过靶向、药物缓释/控释等作用提高药效并降低毒副作用，是解决上述问题的良好手段，而在骨肉瘤治疗领域中缺乏靶向、高效的多功能纳米给药体系的研究。我们前期发现①PRAME抗原特异表达于骨肉瘤细胞膜表面，可作为肿瘤细胞标记物；②GSK-3β作为癌基因通过调节NF-κB通路而调控骨肉瘤细胞活性，是理想的治疗靶点；③通过独创的多流体电射流技术，制备出生物可降解多腔磁性纳米级药物输送颗粒，可作为新型药物载体。本项目拟进一步将化疗药物、GSK-3β/NF-κB靶向抑制剂同时包裹于表面经PRAME抗体修饰的多腔磁性纳米颗粒中，并对其进行鉴定，最后利用多种细胞及动物实验模型，综合评估该纳米药物体系的靶向性、缓释/控释效果、协同杀伤作用、安全性及体内外抗骨肉瘤效果。本项目将为骨肉瘤的治疗提供新思路，并为改善骨肉瘤预后提供新策略。

化疗药物耐药及其毒副作用是骨肉瘤临床治疗的瓶颈，亟需新的治疗策略。纳米给药系统可通过靶向、药物缓释/控释等作用提高药效并降低毒副作用，是解决上述问题的良好手段，而在骨肉瘤治疗领域中缺乏靶向、高效的多功能纳米给药体系的研究。我们在国家自然基金的资助下，通过多流体复合电喷技术，将阿霉素，氨甲喋呤以及顺铂等抗骨肉瘤一线化疗药物，以及GSK3β/NFκB 通路的靶向抑制剂氯化锂，进行了同时并且可控封装，制备出包含多种药物成份的多组分纳米颗粒微胶囊。此方法不仅控制了各组分的分布，而且为活性药物材料的同时包覆提供了很好的条件。基于电喷法的优势，该方法可以很好的扩展到较大的材料范围，并自上而下制备微米尺度甚至纳米尺度的多组分胶囊。另外，该方法避免了繁琐的操作步骤，因而在抗骨肉瘤乃至抗肿瘤生物活性材料等领域展示了很好的应用前景。

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