Mo Jianbin, He Lizhen, Ma Bin, Chen Tianfeng
Department of Chemistry, Jinan University , Guangzhou 510632, China.
ACS Appl Mater Interfaces. 2016 Mar 23;8(11):6811-25. doi: 10.1021/acsami.5b11730. Epub 2016 Mar 8.
The blood-brain barrier (BBB) is the main bottleneck to prevent some macromolecular substance entering the cerebral circulation, resulting the failure of chemotherapy in the treatment of glioma. Cancer nanotechnology displays potent applications in glioma therapy owing to their penetration across BBB and accumulation into the tumor core. In this study, we have tailored the particle size of mesoporous silica nanoparticles (MSNs) through controlling the hydrolysis rate and polycondensation degree of reactants, and optimized the nanosystem that could effectively penetrate BBB and target the tumor tissue to achieve enhanced antiglioma efficacy. The nanoparticle was conjugated with cRGD peptide to enhance its cancer targeting effect, and then used to load antineoplastic doxorubicin. Therefore, the functionalized nanosystem (DOX@MSNs) selectively recognizes and binds to the U87 cells with higher expression level of ανβ3 integrin, sequentially enhancing the cellular uptake and inhibition to glioma cells, especially the particle size at 40 nm. This particle could rapidly enter cancer cells and was difficult to excrete outside the cells, thus leading to high drug accumulation. Furthermore, DOX@MSNs exhibited much higher selectivity and anticancer activity than free DOX and induced the glioma cells apoptosis through triggering ROS overproduction. Interestingly, DOX@MSNs at about 40 nm exhibited stronger permeability across the BBB, and could disrupt the VM-capability of glioma cells by regulating the expression of E-cadherin, FAK, and MMP-2, thus achieving satisfactory antiglioblastoma efficacy and avoiding the unwanted toxic side effects to normal brain tissue. Taken together, these results suggest that tailoring the particle size of MSNs nanosystem could be an effective strategy to antagonize glioblastoma and overcome BBB.
血脑屏障（BBB）是阻止一些大分子物质进入脑循环的主要瓶颈，导致胶质瘤化疗失败。癌症纳米技术因其能够穿透血脑屏障并在肿瘤核心部位蓄积而在胶质瘤治疗中显示出强大的应用潜力。在本研究中，我们通过控制反应物的水解速率和缩聚程度来调整介孔二氧化硅纳米颗粒（MSNs）的粒径，并优化了能够有效穿透血脑屏障并靶向肿瘤组织以实现增强抗胶质瘤疗效的纳米系统。将纳米颗粒与cRGD肽偶联以增强其对癌症的靶向作用，然后用于负载抗肿瘤药物阿霉素。因此，功能化纳米系统（DOX@MSNs）选择性地识别并结合αvβ3整合素表达水平较高的U87细胞，依次增强对胶质瘤细胞的细胞摄取和抑制作用，尤其是粒径为40nm的颗粒。这种颗粒能够迅速进入癌细胞且难以排出细胞外，从而导致药物大量蓄积。此外，DOX@MSNs比游离阿霉素表现出更高的选择性和抗癌活性，并通过触发活性氧的过量产生诱导胶质瘤细胞凋亡。有趣的是，约40nm的DOX@MSNs在血脑屏障上表现出更强的通透性，并可通过调节E-钙黏蛋白、黏着斑激酶和基质金属蛋白酶-2的表达来破坏胶质瘤细胞的血管生成拟态能力，从而实现令人满意的抗胶质母细胞瘤疗效并避免对正常脑组织产生不必要的毒副作用。综上所述，这些结果表明调整MSNs纳米系统的粒径可能是对抗胶质母细胞瘤和克服血脑屏障的有效策略。
