Nanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance.
Nanoparticle-mediated convection-enhanced delivery of a DNA intercalator to gliomas circumvents temozolomide resistance.
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纳米颗粒介导的对流增强 DNA 嵌入剂向神经胶质瘤的传递规避了替莫唑胺耐药性
DOI：
10.1038/s41551-021-00728-7
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发表时间：
2021-09
影响因子：
28.1
通讯作者：
Mark Saltzman W
中科院分区：
文献类型：
--
作者：
Wang Y;Jiang Y;Wei D;Singh P;Yu Y;Lee T;Zhang L;Mandl HK;Piotrowski-Daspit AS;Chen X;Li F;Li X;Cheng Y;Josowitz A;Yang F;Zhao Y;Wang F;Zhao Z;Huttner A;Bindra RS;Xiao H;Mark Saltzman W
在胶质母细胞瘤患者中，对化疗替莫唑胺(TMZ)的耐药性限制了该药物所带来的任何生存益处。在这里，我们展示了对流增强的含有二硫键的纳米颗粒(在肿瘤的还原环境中被裂解)以及包裹奥沙利铂前药和阳离子DNA嵌入剂的纳米颗粒抑制了患者来源的异种移植的TMZ耐药细胞的生长，并阻止了小鼠耐TMZ的人类胶质母细胞瘤的进展，而不会造成任何可检测到的毒性。用阳离子嵌入剂或TMZ处理的胶质瘤细胞系的全基因组RNA图谱和代谢分析显示，每种药物改变的信号和代谢途径都有很大差异。我们的发现表明，具有不同作用机制的抗癌药物与选择性药物释放和对流增强的输送相结合，可能是治疗TMZ耐药胶质瘤的一种翻译策略。
In patients with glioblastoma, resistance to the chemotherapeutic temozolomide (TMZ) limits any survival benefits conferred by the drug. Here we show that the convection-enhanced delivery of nanoparticles containing disulfide bonds (which are cleaved in the reductive environment of the tumour) and encapsulating an oxaliplatin prodrug and a cationic DNA intercalator inhibit the growth of TMZ-resistant cells from patient-derived xenografts, and hinder the progression of TMZ-resistant human glioblastoma tumours in mice without causing any detectable toxicity. Genome-wide RNA profiling and metabolomic analyses of a glioma cell line treated with the cationic intercalator or with TMZ showed substantial differences in the signalling and metabolic pathways altered by each drug. Our findings suggest that the combination of anticancer drugs with distinct mechanisms of action with selective drug release and convection-enhanced delivery may represent a translational strategy for the treatment of TMZ-resistant gliomas.
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