Nanomedicine-based cancer therapies are advancing but the efficacy are hampered by limited knowledge of drug delivery dynamics, including tumor penetration behavior. Utilizing MDA-MB-231 breast tumor spheroids in in vitro experiments and imaging techniques including two-photon microscopy and scanning electron microscopy (SEM), it is demonstrated that quasi-spherical gold nanoparticles penetrate spheroid tissues primarily through the extracellular pathway when the energy-dependent intracellular pathway is blocked. A novel self-developed 3D micro-scale CFD-DEM model integrated with a DLVO sub-model is used to simulate nanoparticle penetration behavior with the extracellular matrix (ECM) considered. The results reveal nanoparticles remain on spheroid surfaces either individually or in small aggregates, with penetration efficacy reducing at amplified concentrations due to increased collisions. Approximately 60 % of intratumoral nanoparticles attach to cells and 40 % to the ECM. Four modes at the particle-scale are identified through the DLVO force and trajectory analysis. This work offers a cost-effective and potential tool for nanoparticles tissue penetration prediction, facilitating interpret and understand the imaging data, and guiding future nanomedicine design.

中文翻译：

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纳米颗粒在肿瘤组织中细胞外渗透的颗粒尺度研究


基于纳米医学的癌症疗法正在取得进展，但由于对药物输送动力学（包括肿瘤渗透行为）的了解有限，其疗效受到阻碍。利用MDA-MB-231乳腺肿瘤球体进行体外实验和成像技术，包括双光子显微镜和扫描电子显微镜（SEM），证明当能量-时，准球形金纳米粒子主要通过细胞外途径穿透球体组织。依赖的细胞内途径被阻断。采用新型自主开发的 3D 微尺度 CFD-DEM 模型与 DLVO 子模型集成，用于模拟考虑细胞外基质 (ECM) 的纳米粒子渗透行为。结果表明，纳米粒子单独或以小聚集体形式保留在球体表面，由于碰撞增加，渗透效率在放大浓度下降低。大约 60% 的瘤内纳米粒子附着在细胞上，40% 附着在 ECM 上。通过 DLVO 力和轨迹分析确定了粒子尺度的四种模式。这项工作为纳米颗粒组织渗透预测提供了一种经济有效且具有潜力的工具，有助于解释和理解成像数据，并指导未来的纳米医学设计。