Houston Zachary H, Bunt Jens, Chen Kok-Siong, Puttick Simon, Howard Christopher B, Fletcher Nicholas L, Fuchs Adrian V, Cui Jiwei, Ju Yi, Cowin Gary, Song Xin, Boyd Andrew W, Mahler Stephen M, Richards Linda J, Caruso Frank, Thurecht Kristofer J
Centre for Advanced Imaging, The University of Queensland, St Lucia, Queensland 4072, Australia.
Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, Queensland 4072, Australia.
ACS Cent Sci. 2020 May 27;6(5):727-738. doi: 10.1021/acscentsci.9b01299. Epub 2020 Apr 28.
Increasing accumulation and retention of nanomedicines within tumor tissue is a significant challenge, particularly in the case of brain tumors where access to the tumor through the vasculature is restricted by the blood-brain barrier (BBB). This makes the application of nanomedicines in neuro-oncology often considered unfeasible, with efficacy limited to regions of significant disease progression and compromised BBB. However, little is understood about how the evolving tumor-brain physiology during disease progression affects the permeability and retention of designer nanomedicines. We report here the development of a modular nanomedicine platform that, when used in conjunction with a unique model of how tumorigenesis affects BBB integrity, allows investigation of how nanomaterial properties affect uptake and retention in brain tissue. By combining different longitudinal imaging techniques (including positron emission tomography and magnetic resonance imaging), we have evaluated the retention of nanomedicines with predefined physicochemical properties (size and surface functionality) and established a relationship between structure and tissue accumulation as a function of a new parameter that measures BBB leakiness; this offers significant advancements in our ability to relate tumor accumulation of nanomedicines to more physiologically relevant parameters. Our data show that accumulation of nanomedicines in brain tumor tissue is better correlated with the of the BBB than actual tumor . This was evaluated by establishing brain tumors using a spontaneous and endogenously derived glioblastoma model providing a unique opportunity to assess these parameters individually and compare the results across multiple mice. We also quantitatively demonstrate that smaller nanomedicines (20 nm) can indeed cross the BBB and accumulate in tumors at earlier stages of the disease than larger analogues, therefore opening the possibility of developing patient-specific nanoparticle treatment interventions in earlier stages of the disease. Importantly, these results provide a more predictive approach for designing efficacious personalized nanomedicines based on a particular patient's condition.
纳米药物在肿瘤组织中不断增加的积累和滞留是一项重大挑战，对于脑肿瘤而言尤其如此，因为通过血管系统进入肿瘤受到血脑屏障（BBB）的限制。这使得纳米药物在神经肿瘤学中的应用通常被认为不可行，其疗效仅限于疾病进展显著且血脑屏障受损的区域。然而，对于疾病进展过程中不断演变的肿瘤 - 脑生理状态如何影响定制纳米药物的通透性和滞留情况，人们了解甚少。我们在此报告一种模块化纳米药物平台的开发，当该平台与肿瘤发生如何影响血脑屏障完整性的独特模型结合使用时，能够研究纳米材料特性如何影响脑组织中的摄取和滞留。通过结合不同的纵向成像技术（包括正电子发射断层扫描和磁共振成像），我们评估了具有预定义物理化学性质（尺寸和表面功能）的纳米药物的滞留情况，并建立了结构与组织积累之间的关系，该关系是作为测量血脑屏障渗漏的一个新参数的函数；这在我们将纳米药物的肿瘤积累与更具生理相关性的参数联系起来的能力方面取得了重大进展。我们的数据表明，纳米药物在脑肿瘤组织中的积累与血脑屏障的[此处原文缺失相关内容]比与实际肿瘤的[此处原文缺失相关内容]具有更好的相关性。这是通过使用自发且内源性衍生的胶质母细胞瘤模型建立脑肿瘤来评估的，该模型提供了一个独特的机会来单独评估这些参数，并在多只小鼠之间比较结果。我们还定量证明，较小的纳米药物（20纳米）在疾病早期确实能够穿过血脑屏障并在肿瘤中积累，而比较大的类似物更早，因此为在疾病早期开发针对特定患者的纳米颗粒治疗干预措施开辟了可能性。重要的是，这些结果为基于特定患者病情设计有效的个性化纳米药物提供了一种更具预测性的方法。
