Harris Michael A, Kuang Huihui, Schneiderman Zachary, Shiao Maple L, Crane Andrew T, Chrostek Matthew R, Tăbăran Alexandru-Flaviu, Pengo Thomas, Liaw Kevin, Xu Beibei, Lin Lucy, Chen Clark C, O'Sullivan M Gerard, Kannan Rangaramanujam M, Low Walter C, Kokkoli Efrosini
Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN 55455, USA.
Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA.
Sci Adv. 2021 Dec 3;7(49):eabl5872. doi: 10.1126/sciadv.abl5872. Epub 2021 Dec 1.
Effective treatment of glioblastoma remains a daunting challenge. One of the major hurdles in the development of therapeutics is their inability to cross the blood-brain tumor barrier (BBTB). Local delivery is an alternative approach that can still suffer from toxicity in the absence of target selectivity. Here, we show that nanotubes formed from self-assembly of ssDNA-amphiphiles are stable in serum and nucleases. After bilateral brain injections, nanotubes show preferential retention by tumors compared to normal brain and are taken up by glioblastoma cells through scavenger receptor binding and macropinocytosis. After intravenous injection, they cross the BBTB and internalize in glioblastoma cells. In a minimal residual disease model, local delivery of doxorubicin showed signs of toxicity in the spleen and liver. In contrast, delivery of doxorubicin by the nanotubes resulted in no systemic toxicity and enhanced mouse survival. Our results demonstrate that ssDNA nanotubes are a promising drug delivery vehicle to glioblastoma.
胶质母细胞瘤的有效治疗仍然是一项艰巨的挑战。治疗方法开发中的一个主要障碍是它们无法穿过血脑肿瘤屏障（BBTB）。局部给药是一种替代方法，但在缺乏靶标选择性的情况下仍可能存在毒性。在这里，我们表明由单链DNA两亲分子自组装形成的纳米管在血清和核酸酶中是稳定的。双侧脑内注射后，与正常脑组织相比，纳米管在肿瘤中显示出优先滞留，并通过清道夫受体结合和巨胞饮作用被胶质母细胞瘤细胞摄取。静脉注射后，它们穿过BBTB并在胶质母细胞瘤细胞内化。在微小残留病模型中，阿霉素的局部给药在脾脏和肝脏中显示出毒性迹象。相比之下，纳米管递送阿霉素不会导致全身毒性，并提高了小鼠的存活率。我们的结果表明，单链DNA纳米管是一种有前途的胶质母细胞瘤药物递送载体。
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