基于粒径智能调节、具有肿瘤微环境响应的脑转移瘤靶向递药系统研究

Tumor therapy is hindered by not only the poor targeting efficiency of drugs but also the poor tumor tissue penetrating ability. The tumor penetrating ability mainly affected by the particle sizes of the nanoparticles. It is a contradiction that nanoparticles with large size (200-500 nm) possess high tumor retention effect but poor tumor penetrating ability, while nanoparticles with small size (5-50 nm) possess low tumor penetrating ability with poor tumor retention effect. This dilemma cannot be conquered by traditional targeting delivery systems. In this project, a novel drug delivery system, DOX-DGL@GNP-An, is designed with tumor microenvironment responsiveness and smart particle size controllability. The system, with a particle size of approximately 200 nm in the blood circulation, can easily be trapped in the tumor and then shrink into about 5 nm which was induced by the highly expressed matrix metalloproteinases-2 in tumor bed, enabling the system with better penetrating ability. Meanwhile, to improve the brain metastasis targeting efficiency, the system is functionalized with angiopep-2, a ligand of low density lipoprotein receptor-related protein that was overexpressed on both blood brain barrier and tumor cells. In conclusion, this system provides a new idea for the treatment for brain metastasis and even for all tumors, which may improve the treatment outcome.

肿瘤治疗不仅面临药物靶向性差的问题，同时存在如何提高肿瘤内穿透的问题。而纳米系统在肿瘤内的滞留性和穿透性与粒径密切相关。大粒径纳米系统（200~500 nm）肿瘤滞留效应强而穿透能力弱，小粒径纳米系统（5~50 nm）组织穿透能力增加但肿瘤滞留效应降低，传统纳米系统无法解决这一矛盾。本项目利用肿瘤部位微环境特性，设计了具有良好肿瘤穿透性的粒径可智能化调节纳米递药系统。该递药系统在血液循环中为200 nm左右，靶向到达肿瘤部位后能有效滞留于肿瘤部位，在肿瘤微环境高表达的基质金属蛋白酶作用下粒径智能化调节为约5 nm，从而具有更好的肿瘤穿透性。同时利用血脑屏障和肿瘤细胞均高表达的低密度脂蛋白受体相关蛋白的特异性配体angiopep-2作为靶向分子，达到脑转移瘤的靶向目的。该策略为脑转移瘤乃至肿瘤的靶向诊断和治疗提供了新思路，有望提高对脑转移瘤的治疗效果，具有重要的研究价值和潜在的应用意义。

肿瘤治疗不仅面临药物靶向性差的问题，同时存在如何提高肿瘤内穿透的问题。而纳米系统在肿瘤内的滞留性和穿透性与粒径密切相关。大粒径纳米系统（200~500 nm）肿瘤滞留效应强而穿透能力弱，小粒径纳米系统（5~50 nm）组织穿透能力增加但肿瘤滞留效应降低，传统纳米系统无法解决这一矛盾。本项目利用肿瘤部位微环境高表达基质金属蛋白酶2（MMP2）特性，设计了具有良好肿瘤穿透性的粒径可智能化调节纳米递药系统。该递药系统以小粒径的树枝状分子DGL和金纳米粒（AuNP）为药物载体，将其修饰在可被MMP2降解的明胶纳米粒（GNP）表面，并进而进行靶向分子Angiopep-2、iRGD、RRGD等的修饰，构成了可降解纳米递药系统。这些递药系统在血液循环中为200 nm左右，靶向到达肿瘤部位后能有效滞留于肿瘤部位，在肿瘤微环境高表达的MMP2作用下粒径智能化调节为约50 nm，从而具有更好的肿瘤穿透性。体内外肿瘤球穿透实验和凝胶渗透实验均证明了MMP2响应性的渗透性增加特性，同时细胞摄取和体内成像实验证明该系统具有良好的肿瘤靶向性和蓄积能力，并能够有效分布于肿瘤的缺血管区域，体现出良好的靶向性、滞留性和渗透性。综合这些因素，该纳米系统体现出良好的抗肿瘤效果。该策略为周围系统肿瘤及脑肿瘤的靶向诊断和治疗提供了新思路，有望提高对肿瘤和脑肿瘤的治疗效果，具有重要的研究价值和潜在的应用意义。

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