Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles.
Enhanced efficacy of combined temozolomide and bromodomain inhibitor therapy for gliomas using targeted nanoparticles.
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DOI：
10.1038/s41467-018-04315-4
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发表时间：
2018-05-18
影响因子：
16.6
通讯作者：
Hammond PT
中科院分区：
文献类型：
--
作者：
Lam FC;Morton SW;Wyckoff J;Vu Han TL;Hwang MK;Maffa A;Balkanska-Sinclair E;Yaffe MB;Floyd SR;Hammond PT
胶质母细胞瘤（GBM）的有效治疗受到血脑屏障（BBB）的存在和对单药治疗的快速耐药性的限制。为了解决这些问题，我们开发了一种转铁蛋白功能化纳米颗粒（Tf-NP），它可以提供双重联合疗法。使用活体成像，我们展示了 Tf-NP 穿越小鼠完整 BBB 的能力，以及在两种 GBM 颅内原位模型中实现直接肿瘤结合的能力。用载有替莫唑胺和溴结构域抑制剂 JQ1 的 Tf-NP 治疗荷瘤小鼠，会导致 DNA 损伤和细胞凋亡增加，与同等游离药物剂量相比，肿瘤负荷减少 1.5 至 2 倍，存活率相应增加。用 Tf-NP 负载药物治疗的免疫活性小鼠也显示出免受全身药物毒性影响的保护作用，证明了该纳米级平台为神经胶质瘤和其他中枢神经系统肿瘤提供新型联合疗法的临床前潜力。血脑屏障常常限制胶质母细胞瘤治疗的有效实施。在这项研究中，作者开发了转铁蛋白功能化的纳米颗粒，能够穿过完整的血脑屏障，并向患有神经胶质瘤的小鼠提供替莫唑胺和溴结构域抑制剂的联合治疗。
Effective treatment for glioblastoma (GBM) is limited by the presence of the blood–brain barrier (BBB) and rapid resistance to single agent therapies. To address these issues, we developed a transferrin-functionalized nanoparticle (Tf-NP) that can deliver dual combination therapies. Using intravital imaging, we show the ability of Tf-NPs to traverse intact BBB in mice as well as achieve direct tumor binding in two intracranial orthotopic models of GBM. Treatment of tumor-bearing mice with Tf-NPs loaded with temozolomide and the bromodomain inhibitor JQ1 leads to increased DNA damage and apoptosis that correlates with a 1.5- to 2-fold decrease in tumor burden and corresponding increase in survival compared to equivalent free-drug dosing. Immunocompetent mice treated with Tf-NP-loaded drugs also show protection from the effects of systemic drug toxicity, demonstrating the preclinical potential of this nanoscale platform to deliver novel combination therapies to gliomas and other central nervous system tumors. The blood-brain barrier often limits effective delivery of treatments for glioblastoma . In this study, the authors develop transferrin-functionalized nanoparticles able to traverse the intact blood-brain barrier and deliver combination temozolomide and bromodomain inhibitor therapy to glioma-bearing mice.
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影响因子：
158.5
作者：
Stupp, R;Mason, WP;Ryan, G
通讯作者：
Ryan, G
DOI：
10.1158/1078-0432.ccr-12-3066
发表时间：
2013-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cheng Z;Gong Y;Ma Y;Lu K;Lu X;Pierce LA;Thompson RC;Muller S;Knapp S;Wang J
通讯作者：
Wang J
影响因子：
64.5
作者：
Matzuk MM;McKeown MR;Filippakopoulos P;Li Q;Ma L;Agno JE;Lemieux ME;Picaud S;Yu RN;Qi J;Knapp S;Bradner JE
通讯作者：
Bradner JE
中枢神经系统疾病的纳米技术 - 新颖的疗法。
影响因子：
38.1
作者：
Srikanth, Maya;Kessler, John A.
通讯作者：
Kessler, John A.
影响因子：
8.8
作者：
Bolden JE;Tasdemir N;Dow LE;van Es JH;Wilkinson JE;Zhao Z;Clevers H;Lowe SW
通讯作者：
Lowe SW