Center for Nanomedicine, Department of Ophthalmology, Wilmer Eye Institute Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, United States.
Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland 21218, United States.
Biomacromolecules. 2020 Dec 14;21(12):5148-5161. doi: 10.1021/acs.biomac.0c01270. Epub 2020 Oct 28.
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 . , 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.
胶质母细胞瘤由于向大脑和实体肿瘤输送药物存在挑战，导致死亡率居高不下。这种双重障碍需要高剂量的系统治疗，从而导致严重的脱靶毒性。最近，树状高分子纳米药物（无配体）已显示出从全身循环靶向脑瘤中特定细胞的潜力，以提高疗效并减轻全身毒性。本文提出了一种树突状-雷帕霉素缀合物（D-Rapa），可从全身给药特异性靶向胶质母细胞瘤中的肿瘤相关巨噬细胞（TAMs）。D-Rapa 可改善激活的 TAMs 中促肿瘤表达的抑制作用，并增强雷帕霉素对神经胶质瘤细胞的抗增殖作用。D-Rapa 特异性定位于 TAMs 内，作为储存库将雷帕霉素释放到肿瘤微环境中。这种靶向递药策略可显著降低荷瘤负担，并减轻具有挑战性的、临床相关的同源原位胶质母细胞瘤模型中的全身毒性，这表明树突状高分子作为靶向免疫疗法具有改善胶质母细胞瘤治疗的巨大潜力，而这仍然是一个未满足的需求。
