Glioblastoma exhibits high mortality rates due to challenges with drug delivery to the brain and into solid tumors. This two-pronged barrier necessitates high doses of systemic therapies, resulting in significant off-target toxicities. Recently, dendrimer-nanomedicines (without ligands) have shown promise for targeting specific cells in brain tumors from systemic circulation, for improved efficacy and amelioration of systemic toxicities. A dendrimer–rapamycin conjugate (D-Rapa) is presented here that specifically targets tumor-associated macrophages (TAMs) in glioblastoma from systemic administration. D-Rapa improves suppression of pro-tumor expression in activated TAMs and antiproliferative properties of rapamycin in glioma cells in vitro. In vivo, D-Rapa localizes specifically within TAMs, acting as depots to release rapamycin into the tumor microenvironment. This targeted delivery strategy yields improved reduction in tumor burden and systemic toxicities in a challenging, clinically relevant orthotopic syngeneic model of glioblastoma, demonstrating the significant potential of dendrimers as targeted immunotherapies for improving glioblastoma treatment, still an unmet need.

中文翻译：

---

树枝状大分子介导雷帕霉素靶向靶向递送至肿瘤相关巨噬细胞改善了胶质母细胞瘤的全身治疗

胶质母细胞瘤由于向大脑和实体瘤的药物输送挑战而表现出高死亡率。这种两管齐下的屏障需要高剂量的全身疗法，从而导致明显的脱靶毒性。最近，树枝状大分子药物（无配体）已显示出有望从全身循环中靶向脑肿瘤中特定细胞的作用，以改善疗效并改善全身毒性。本文介绍了一种树状聚合物-雷帕霉素结合物（D-Rapa），其特异性靶向全身性胶质母细胞瘤中的肿瘤相关巨噬细胞（TAM）。D-Rapa在体外可改善激活的TA​​M中肿瘤表达的抑制和雷帕霉素在神经胶质瘤细胞中的抗增殖特性。体内，D-Rapa特异地定位在TAM内，充当将雷帕霉素释放到肿瘤微环境中的贮库。这种靶向递送策略在具有挑战性，临床相关的原位胶质母细胞瘤同基因模型中可改善肿瘤负荷和降低系统毒性，证明树状大分子作为靶向免疫疗法改善胶质母细胞瘤治疗的巨大潜力，但仍未得到满足。