砒霜活性成分三氧化二砷脂质囊纳米粒脑胶质瘤深部渗透靶向递药系统研究

Due to the dual obstruction of blood-brain barrier(BBB) and intratumoral collagen-rich environment on drug penetration, it's difficult for drugs and drug delivery systems to efficiently reach the deep of glioma tumor. Arsenic trioxide (ATO) is the active ingredients of traditional Chinese medicine White arsenic, which has good effects on the treatment of glioma, however, because of poor fat-soluble character, difficulty to penetrate BBB and toxicity, its utilization has been limited. Based on the biological characteristics of gliomas and tumor microenvironment, the project will build a glioma targeted delivery system which is constructed by ATO and ethylmaleimide (NEM) loaded Angiopep-2-modified silica liposparticles, and has dual function of "targeted delivery" and "deep penetration". The system is targeted to glioma after penetrating the BBB, then release NEM to activate the local MMP zymogen according to the pH, ablate the collagen at fixed-point and promote deep-penetration of ATO. The project explores the characteristics and mechanisms of active targeting and deep drug delivery from the molecular, cellular and animal levels, and studies the antitumor effect and neurotoxicity. The project provides new ideas and methods for construction of glioma targeted delivery system, and has important reference in the application of ATO for clinical treatment of glioma.

脑胶质瘤恶性程度高、侵袭性强，因血脑屏障和肿瘤基质胶原的双重阻碍，药物及递药体系均难以高效到达胶质瘤深部；而中药砒霜及其有效活性成分三氧化二砷(ATO)对脑胶质瘤治疗效果良好，但由于ATO脂溶性差、透血脑屏障难、毒性大等问题限制其应用。本项目利用肿瘤微环境和胶质瘤生物学特性，拟构建一种兼具"靶向递药"和"深部渗透"双重功能的脑胶质瘤递药系统，以Angiopep-2修饰的二氧化硅脂质囊纳米粒为载体，双载ATO和N-乙基马来酰亚胺(NEM)。该体系透过血脑屏障后靶向脑胶质瘤，pH响应释放NEM激活局部MMP酶原，定点消融基质胶原，促使ATO深部渗透。从分子、细胞、动物三个层面探讨主动靶向与深部渗透特性及其机制，并进行抗肿瘤药效学与神经毒性的研究。本项目的完成将为脑胶质瘤药物递送系统的构建提供新思路和新方法，对于ATO用于脑胶质瘤治疗也具有重要的借鉴意义。

脑胶质瘤因恶性程度高、侵袭性强、治疗效果不佳等一直是研究难点，而传统矿物药砒霜活性成分三氧化二砷（ATO）对脑胶质瘤具有良好的治疗效果，但由于ATO存在脂溶性差、透血脑屏障难、体内分布缺乏特异性、组织毒性大等问题而在临床应用中受到严重限制。其具有快速的肾清除率、高血清蛋白结合率、肿瘤部位药物浓度低以及肝功能不全等药物不良反应，脑内血药浓度“峰谷”波动亦会引起颅内中枢组织的严重不良反应，这些因素都极大限制了三氧化二砷在脑胶质瘤治疗中的应用。本项目构建了兼具“靶向递药”和“恒速释放”双重功能的脑胶质瘤“靶-控”递药系统，通过“靶向递药”使抗肿瘤药物能跨血脑屏障入脑，选择性地浓集于肿瘤病灶，减少向其它正常组织的分布；通过“恒速释放”使药物在脑胶质瘤病灶以零级速度（恒定速度）持续释药，获得稳定的血药浓度，减少了毒副作用。以期通过现代靶向新技术和控释新技术的联合使用，提高抗肿瘤药物的生物利用率，减少用药剂量，获得高效、长效、副作用小的临床治疗效果。另外三氧化二砷脑胶质瘤靶向递药系统取得客观的药效以后，研究进一步拓展至实体瘤（肝癌）的治疗。本研究为三氧化二砷治疗脑胶质瘤等实体瘤提供了新的思路与理论基础。