A predictive microfluidic model of human glioblastoma to assess trafficking of blood-brain barrier-penetrant nanoparticles.
A predictive microfluidic model of human glioblastoma to assess trafficking of blood-brain barrier-penetrant nanoparticles.
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DOI：
10.1073/pnas.2118697119
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发表时间：
2022-06-07
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
血脑屏障代表了胶质母细胞瘤治疗的主要治疗挑战，并且对于概括人类生物学并预测体内反应的体外模型存在未满足的需求。在这里，我们提出了一个微流体模型的血管化胶质母细胞瘤具有肿瘤球体直接接触自组装血管网络，包括人内皮细胞，星形胶质细胞和周细胞。该模型旨在加速靶向纳米治疗药物的开发，并能够严格评估一组表面功能化纳米颗粒，这些纳米颗粒旨在利用肿瘤相关血管系统中过表达的受体。与平行的体内数据相比，体外模型中的运输和功效数据有利，突出了血管化胶质母细胞瘤模型用于治疗开发的实用性。血脑屏障是治疗高级别胶质瘤的一个重大挑战，我们对药物转运通过这一关键生物界面的理解仍然有限。为了推进神经胶质瘤的临床前治疗开发，迫切需要具有现实血脑屏障血管系统的预测性体外模型。在这里，我们报告了一个血管化的人多形性胶质母细胞瘤（GBM）模型，该模型在微流体装置中准确地重现了具有自组装内皮细胞，星形胶质细胞和周细胞的脑肿瘤血管系统，以研究靶向纳米治疗药物穿过血脑屏障并进入GBM细胞的运输。使用模块化逐层组装，我们用GBM靶向基序功能化纳米颗粒的表面，以改善向肿瘤的运输。我们使用活体成像直接比较了体外平台中的纳米颗粒转运与小鼠脑毛细血管中的转运，验证了该平台模拟体内血脑屏障转运的能力。我们通过封装顺铂研究了功能化纳米颗粒的治疗潜力，并在体外和体内原位异种移植模型中显示了这些GBM靶向纳米颗粒的改善功效。我们的血管化GBM模型代表了一个重要的生物材料进步，使脑肿瘤血管系统的深入研究和加速靶向纳米治疗的发展。
The blood–brain barrier represents a major therapeutic challenge for the treatment of glioblastoma, and there is an unmet need for in vitro models that recapitulate human biology and are predictive of in vivo response. Here, we present a microfluidic model of vascularized glioblastoma featuring a tumor spheroid in direct contact with self-assembled vascular networks comprising human endothelial cells, astrocytes, and pericytes. This model was designed to accelerate the development of targeted nanotherapeutics and enabled rigorous assessment of a panel of surface-functionalized nanoparticles designed to exploit a receptor overexpressed in tumor-associated vasculature. Trafficking and efficacy data in the in vitro model compared favorably to parallel in vivo data, highlighting the utility of the vascularized glioblastoma model for therapeutic development. The blood–brain barrier represents a significant challenge for the treatment of high-grade gliomas, and our understanding of drug transport across this critical biointerface remains limited. To advance preclinical therapeutic development for gliomas, there is an urgent need for predictive in vitro models with realistic blood–brain-barrier vasculature. Here, we report a vascularized human glioblastoma multiforme (GBM) model in a microfluidic device that accurately recapitulates brain tumor vasculature with self-assembled endothelial cells, astrocytes, and pericytes to investigate the transport of targeted nanotherapeutics across the blood–brain barrier and into GBM cells. Using modular layer-by-layer assembly, we functionalized the surface of nanoparticles with GBM-targeting motifs to improve trafficking to tumors. We directly compared nanoparticle transport in our in vitro platform with transport across mouse brain capillaries using intravital imaging, validating the ability of the platform to model in vivo blood–brain-barrier transport. We investigated the therapeutic potential of functionalized nanoparticles by encapsulating cisplatin and showed improved efficacy of these GBM-targeted nanoparticles both in vitro and in an in vivo orthotopic xenograft model. Our vascularized GBM model represents a significant biomaterials advance, enabling in-depth investigation of brain tumor vasculature and accelerating the development of targeted nanotherapeutics.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
影响因子：
16.1
作者：
通讯作者：
--
DOI：
10.1158/1078-0432.ccr-15-0013
发表时间：
2015-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dreaden EC;Kong YW;Morton SW;Correa S;Choi KY;Shopsowitz KE;Renggli K;Drapkin R;Yaffe MB;Hammond PT
通讯作者：
Hammond PT
影响因子：
4.6
作者：
Edington CD;Chen WLK;Geishecker E;Kassis T;Soenksen LR;Bhushan BM;Freake D;Kirschner J;Maass C;Tsamandouras N;Valdez J;Cook CD;Parent T;Snyder S;Yu J;Suter E;Shockley M;Velazquez J;Velazquez JJ;Stockdale L;Papps JP;Lee I;Vann N;Gamboa M;LaBarge ME;Zhong Z;Wang X;Boyer LA;Lauffenburger DA;Carrier RL;Communal C;Tannenbaum SR;Stokes CL;Hughes DJ;Rohatgi G;Trumper DL;Cirit M;Griffith LG
通讯作者：
Griffith LG
影响因子：
28.4
作者：
Brown TJ;Brennan MC;Li M;Church EW;Brandmeir NJ;Rakszawski KL;Patel AS;Rizk EB;Suki D;Sawaya R;Glantz M
通讯作者：
Glantz M