Mitochondria mediate critical cellular processes, including proliferation, apoptosis, and immune responses; as such, their dysfunction is pathogenic in many neurodegenerative disorders and cancers. In glioblastoma, targeted delivery of mitochondria-focused anticancer therapies has failed to translate into clinical success due to the nonspecific cellular localization, heterogeneity of receptor expression across patients, poor transport across biological barriers to reach the brain, tumor, and mitochondria, and systemic side effects. Strategies that can overcome brain and solid tumor barriers and selectively target mitochondria within specific cell types may lead to improvements in glioblastoma treatment. Developments in dendrimer-mediated nanomedicines have shown promise targeting tumor-associated macrophages (TAMs) in glioblastoma, following systemic administration. Here, we present a novel dendrimer conjugated to the translocator protein (18 kDa) (TSPO) ligand 5,7-dimethylpyrazolo[1,5-α]pyrimidin-3-ylacetamide (DPA). We developed a clickable DPA for conjugation on the dendrimer surface and demonstrated in vitro that the dendrimer-DPA conjugate (D-DPA) significantly increases dendrimer colocalization with mitochondria. Compared to free TSPO ligand PK11195, D-DPA stimulates greater antitumor immune signaling. In vivo, we show that D-DPA targets mitochondria specifically within TAMs following systemic administration. Our results demonstrate that dendrimers can achieve TAM-specific targeting in glioblastoma and can be further modified to target specific intracellular compartments for organelle-specific drug delivery.

中文翻译：

---

使用树枝状大分子缀合的 TSPO 配体靶向肿瘤相关巨噬细胞中的线粒体，刺激胶质母细胞瘤中的抗肿瘤信号传导。


线粒体介导关键的细胞过程，包括增殖、凋亡和免疫反应；因此，它们的功能障碍是许多神经退行性疾病和癌症的致病因素。在胶质母细胞瘤中，由于非特异性细胞定位、患者受体表达的异质性、跨生物屏障到达大脑、肿瘤和线粒体的运输不良以及全身副作用，以线粒体为重点的抗癌疗法未能转化为临床成功。影响。能够克服脑部和实体瘤屏障并选择性地靶向特定细胞类型内的线粒体的策略可能会改善胶质母细胞瘤的治疗。树枝状大分子介导的纳米药物的发展已显示出在全身给药后靶向胶质母细胞瘤中的肿瘤相关巨噬细胞（TAM）的前景。在这里，我们提出了一种与易位蛋白（18 kDa）（TSPO）配体5,7-二甲基吡唑并[1,5-α]嘧啶-3-基乙酰胺（DPA）缀合的新型树枝状聚合物。我们开发了一种可点击的 DPA，用于在树枝状聚合物表面缀合，并在体外证明树枝状聚合物-DPA 缀合物 (D-DPA) 显着增加了树枝状聚合物与线粒体的共定位。与游离 TSPO 配体 PK11195 相比，D-DPA 可刺激更强的抗肿瘤免疫信号传导。在体内，我们表明，全身给药后，D-DPA 特异性靶向 TAM 内的线粒体。我们的结果表明，树枝状聚合物可以在胶质母细胞瘤中实现 TAM 特异性靶向，并且可以进一步修饰以靶向特定的细胞内区室，以实现细胞器特异性药物递送。