Wong Andrew D, Russell Luisa M, Katt Moriah E, Searson Peter C
Institute for Nanobiotechnology (INBT), Johns Hopkins University, 100 Croft Hall, 3400 North Charles Street, Baltimore, Maryland 21218, United States.
Department of Materials Science and Engineering, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, United States.
ACS Biomater Sci Eng. 2019 Feb 11;5(2):633-643. doi: 10.1021/acsbiomaterials.8b00877. Epub 2018 Dec 31.
Numerous approaches have been employed to improve the efficacy of drug and gene delivery systems, but their strategic development is hindered by a lack of mechanistic understanding and assessment of drug transport and action. Optimizing the efficiency of a drug delivery system requires a detailed understanding of the pharmacokinetics, transendothelial transport, distribution at the tumor site, and uptake in target cells. Elucidating transport kinetics and rate-limiting steps in animal models can be extremely challenging, while platforms often fail to recapitulate the complexities of drug transport . To recapitulate the critical aspects of delivery of anticancer agents, we have developed a 3D tissue-engineered microvessel model of the tumor microenvironment. Our model consists of single MDA-MB-231 breast cancer cells embedded within a collagen matrix that surrounds a perfusable cylindrical microvessel lined with human endothelial cells. Here we compare transport and action of free doxorubicin and Doxil, a liposomal formulation of doxorubicin. We show that the mode of drug delivery influences uptake in the vessel endothelium and tumor cells. Through quantification of endothelial and tumor cell proliferation, apoptosis, and motility, we profile the kinetics of drug action with mechanisms of drug transport across the vessel lumen and into the surrounding matrix. Our model can be customized to mimic specific tumor microenvironments and disease states within a physiologically relevant microfluidic platform and provides a basis for characterizing and optimizing drug delivery systems.
人们已经采用了多种方法来提高药物和基因递送系统的疗效，但其战略发展受到对药物转运和作用缺乏机理理解和评估的阻碍。优化药物递送系统的效率需要详细了解药代动力学、跨内皮转运、在肿瘤部位的分布以及在靶细胞中的摄取。在动物模型中阐明转运动力学和限速步骤极具挑战性，而相关平台往往无法重现药物转运的复杂性。为了重现抗癌药物递送的关键方面，我们开发了一种肿瘤微环境的三维组织工程微血管模型。我们的模型由单个MDA-MB-231乳腺癌细胞嵌入胶原蛋白基质组成，该基质围绕着内衬人内皮细胞的可灌注圆柱形微血管。在这里，我们比较了游离阿霉素和阿霉素脂质体（Doxil）的转运和作用。我们表明，药物递送方式会影响血管内皮细胞和肿瘤细胞的摄取。通过对内皮细胞和肿瘤细胞增殖、凋亡和运动性的量化，我们描绘了药物作用的动力学以及药物穿过血管腔并进入周围基质的转运机制。我们的模型可以定制，以在生理相关的微流控平台中模拟特定的肿瘤微环境和疾病状态，并为表征和优化药物递送系统提供基础。
