基于冰片开窍和姜黄素肿瘤微环境调控作用的多策略靶向纳米系统的构建及其抗脑干胶质瘤研究

Brain stem glioma is one of the most incurable neural tumors because of its high mortality and inoperability. A sound chemotherapy for brain stem glioma should be able to cross the blood brain barrier and the blood brain tumor barrier, then penetrate into the tumor core. Our previous research demonstrated that borneol modified nanoparticle can effectively deliver drugs to the brain stem after intranasal administration, but without tumor targeting ability. So we suppose, we can combine the brain stem targeting effect of borneol with the tumor targeting effect of R8-dGR and develop a dual-targeting biodegradable nanopartice to encapsulate both antineoplastics cisplatin, and curcumin, a traditional Chinese medicine that can remodel the tumor microenvironment, thus enhancing the therapeutic effect on brain stem glioma. The brain guiding effect of borneol will bring the nanoparticles into brain stem, after which the R8-dGR will deliver the nanoparticles to the tumor site. The remodeling effect of curcumin on tumor microenvirnment will facilitate the penetration of nanoparticles into the tumor core, thus enhancing the antitumor effect of cisplatin. The novel borneol/R8-dGR modified curcumin/cisplatin nanoparticle will provide a new non-invasive strategy for treating the deadly brain stem glioma. Exploring the synergistic targeting effect of borneol and R8-dGR, the remodeling effect of curcumin on tumor microenvirnment, as well as the synergistic effect of curcumin and cisplatin on inhibiting brain stem glioma, will bring new thoughts to the ways of combing traditional Chinese medicine with antineoplastics for better tumor targeting therapy.

脑干胶质瘤因其高致死率，无法手术一直是神经肿瘤治疗的难点。脑干胶质瘤化疗药物需要能跨越血脑屏障，血脑肿瘤屏障，并渗透至肿瘤内部起效。我们前期研究发现，冰片修饰纳米粒经鼻腔给药能有效将药物递送入脑干，但对肿瘤无特异靶向性。因此我们设想：将冰片修饰的脑干靶向性和R8-dGR肽的肿瘤靶向性相结合，构建双级靶向纳米递药系统，共同包载肿瘤微环境调控药物姜黄素和化疗药顺铂，以提高对脑干胶质瘤的治疗效果。冰片的开窍作用将药物递送入脑干，R8-dGR肽使进入脑干的药物靶向于胶质瘤细胞，姜黄素的肿瘤微环境调控作用能有效改善纳米粒的肿瘤内渗透，提高化疗药顺铂的抗肿瘤效果。冰片/R8-dGR共修饰姜黄素/顺铂双级靶向纳米递药系统将为脑干胶质瘤的治疗提供一种新的非侵入性治疗手段。同时探讨冰片和R8-dGR的协同靶向作用，姜黄素对胶质瘤微环境的调控作用及其协同抗肿瘤机理，将为中西药结合靶向肿瘤治疗提供新的研究思路。

脑干胶质瘤手术致死率高，临床缺乏有效的治疗手段。本项目将冰片修饰纳米粒经鼻给药的脑干靶向性和R8-dGR肽的肿瘤靶向性相结合，构建了一种新型冰片/R8-dGR肽共修饰、顺铂/姜黄素共载药的脑干胶质瘤靶向纳米治疗系统（Bo/R8dGR-NP）。对其体内外脑干胶质瘤靶向性、靶向机理、体内外抗脑干胶质瘤药效学及经鼻给药安全性进行了评价。. 制得的Bo/R8dGR-NP粒径在150 nm左右，体外靶向性试验结果证实其在鼻腔粘膜模型和肿瘤细胞模型上具有更好的摄取，且Bo和R8dGR两种靶向分子在网格蛋白介导的内吞、胞饮等途径上有协同作用。肿瘤球模型试验证实Bo/R8dGR-NP具有更好的肿瘤渗透能力。Calu-3/GL261经鼻转运体外脑胶质瘤模型研究证实Bo/R8dGR-NP具有更好的经鼻入脑跨膜转运能力。Bo/R8dGR-NP纳米粒可以显著抑制GL261细胞的活力，与Cur/Cis混合溶液及Cis溶液组相比存在显著性差异。体内活体成像结果证实Bo/R8dGR-NP具更好的脑干靶向性。机理研究结果表明该系统通过纳米粒表面修饰的R8dGR肽与αvβ3受体的结合，及Bo对肿瘤细胞p-gp表达的抑制发挥更好的脑干胶质瘤靶向性能。并可通过Bo对鼻腔粘膜细胞ZO-1和Occludin蛋白的抑制而增加鼻粘膜通透性。药效学研究结果表明，该系统能显著提高模型化疗药物顺铂对于小鼠脑干胶质瘤的治疗效果，降低其副作用。并能显著提高荷瘤小鼠的生存时间,体内外安全性佳。. Bo/R8dGR-NP多策略靶向纳米系统集传统引经药Bo和鼻腔给药的BBB靶向性，多肽R8-dGR的肿瘤靶向性，姜黄素的肿瘤微环境调控性能于一身，为手术治疗困难，放化疗效果不佳的脑干胶质瘤的治疗提供了一种新的非侵入性治疗手段。为中西药结合抗肿瘤治疗提供了一种新的方法和思路。