Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology (BIST), Carrer Baldiri Reixac 15-21, 08024 Barcelona, Spain.
Department of Biomedical Engineering, Institute for Complex Molecular Systems (ICMS), Eindhoven University of Technology, 5612AZ Eindhoven, The Netherlands.
ACS Appl Bio Mater. 2021 Jan 18;4(1):669-681. doi: 10.1021/acsabm.0c01209. Epub 2020 Dec 23.
The performance of supramolecular nanocarriers as drug delivery systems depends on their stability in the complex and dynamic biological media. After administration, nanocarriers are challenged by physiological barriers such as shear stress and proteins present in blood, endothelial wall, extracellular matrix, and eventually cancer cell membrane. While early disassembly will result in a premature drug release, extreme stability of the nanocarriers can lead to poor drug release and low efficiency. Therefore, comprehensive understanding of the stability and assembly state of supramolecular carriers in each stage of delivery is the key factor for the rational design of these systems. One of the main challenges is that current 2D models do not provide exhaustive information, as they fail to recapitulate the 3D tumor microenvironment. This deficiency in the 2D model complexity is the main reason for the differences observed when testing the performance of supramolecular nanocarriers. Herein, we present a real-time monitoring study of self-assembled micelles stability and extravasation, combining spectral confocal microscopy and a microfluidic cancer-on-a-chip. The combination of advanced imaging and a reliable 3D model allows tracking of micelle disassembly by following the spectral properties of the amphiphiles in space and time during the crucial steps of drug delivery. The spectrally active micelles were introduced under flow and their position and conformation continuously followed by spectral imaging during the crossing of barriers, revealing the interplay between carrier structure, micellar stability, and extravasation. Integrating the ability of the micelles to change their fluorescent properties when disassembled, spectral confocal imaging and 3D microfluidic tumor blood vessel-on-a-chip resulted in the establishment of a robust testing platform suitable for real-time imaging and evaluation of supramolecular drug delivery carrier's stability.
超分子纳米载体作为药物传递系统的性能取决于其在复杂和动态的生物介质中的稳定性。给药后，纳米载体受到生理屏障的挑战，如血液中存在的剪切应力和蛋白质、内皮壁、细胞外基质，最终还有癌细胞膜。早期的解体将导致药物过早释放，而纳米载体的极端稳定性会导致药物释放不良和效率低下。因此，全面了解超分子载体在传递过程的每个阶段的稳定性和组装状态是这些系统合理设计的关键因素。主要挑战之一是，当前的 2D 模型没有提供详尽的信息，因为它们无法重现 3D 肿瘤微环境。2D 模型复杂性的这种不足是观察到超分子纳米载体性能测试差异的主要原因。在此，我们结合光谱共焦显微镜和微流控癌症芯片，进行了自组装胶束稳定性和渗出的实时监测研究。先进成像与可靠 3D 模型的结合，可以通过在药物传递的关键步骤中随时间和空间跟踪两亲物的光谱特性，跟踪胶束的解体。在流动条件下引入光谱活性胶束，并在跨越屏障的过程中通过光谱成像连续跟踪其位置和构象，揭示载体结构、胶束稳定性和渗出之间的相互作用。将胶束在解体时改变其荧光特性的能力与光谱共焦成像和 3D 微流控肿瘤血管芯片相结合，建立了一个强大的测试平台，适用于超分子药物传递载体稳定性的实时成像和评估。
