Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
J Control Release. 2021 Sep 10;337:179-192. doi: 10.1016/j.jconrel.2021.07.018. Epub 2021 Jul 16.
Glioblastoma is among the most aggressive forms of cancers, with a median survival of just 15-20 months for patients despite maximum clinical intervention. The majority of conventional anti-cancer therapies fail due to associated off-site toxicities which can be addressed by developing target-specific drug delivery systems. Advances in nanotechnology have provided targeted systems to overcome drug delivery barriers associated with brain and other types of cancers. Dendrimers have emerged as promising vehicles for targeted drug and gene delivery. Dendrimer-mediated targeting strategies can be further enhanced through the addition of targeting ligands to enable receptor-specific interactions. Here, we explore the sugar moieties as ligands conjugated to hydroxyl-terminated polyamidoamine dendrimers to leverage altered metabolism in cancer and immune targeting. Using a highly facile click chemistry approach, we modified the surface of dendrimers with glucose, mannose, or galactose moieties in a well-defined manner, to target upregulated sugar transporters in the context of glioblastoma. We show that glucose modification significantly enhanced targeting of tumor-associated macrophages (TAMs) and microglia by increasing brain penetration and cellular internalization, while galactose modification shifts targeting away from TAMs towards galectins on glioblastoma tumor cells. Mannose modification did not alter TAMs and microglia targeting of these dendrimers, but did alter their kinetics of accumulation within the GBM tumor. The whole body biodistribution was largely similar between the systems. These results demonstrate that dendrimers are versatile delivery vehicles that can be modified to tailor their targeting for the treatment of glioblastoma and other cancers.
胶质母细胞瘤是最具侵袭性的癌症之一，尽管进行了最大程度的临床干预，患者的中位生存期仅为 15-20 个月。由于相关的非靶向毒性，大多数传统的抗癌疗法都失败了，这些毒性可以通过开发靶向药物递送系统来解决。纳米技术的进步为克服与大脑和其他类型癌症相关的药物递送障碍提供了靶向系统。树突状聚合物已成为靶向药物和基因递送的有前途的载体。通过向树突状聚合物添加靶向配体，可以进一步增强树突状聚合物介导的靶向策略，以实现受体特异性相互作用。在这里，我们探索了糖基作为与羟基封端的聚酰胺胺树突状聚合物缀合的配体，以利用癌症和免疫靶向中的改变代谢。使用高度简便的点击化学方法，我们以明确定义的方式用葡萄糖、甘露糖或半乳糖修饰树突状聚合物的表面，以针对胶质母细胞瘤中上调的糖转运蛋白进行靶向。我们表明，葡萄糖修饰通过增加脑穿透和细胞内化，显著增强了对肿瘤相关巨噬细胞 (TAMs) 和小胶质细胞的靶向作用，而半乳糖修饰将靶向作用从 TAMs 转移到胶质母细胞瘤肿瘤细胞上的半乳糖结合蛋白上。甘露糖修饰不会改变这些树突状聚合物对 TAMs 和小胶质细胞的靶向作用，但会改变它们在 GBM 肿瘤内的积累动力学。全身生物分布在这些系统之间基本相似。这些结果表明，树突状聚合物是多功能的递送载体，可以进行修饰以针对胶质母细胞瘤和其他癌症的治疗来调整其靶向作用。
