Targeted nanoparticles are increasingly being engineered for the treatment of cancer. By design, they can passively accumulate in tumors, selectively bind to targets in their environment, and deliver localized treatments. However, the penetration of targeted nanoparticles deep into tissue can be hindered by their slow diffusion and a high binding affinity. As a result, they often localize to areas around the vessels from which they extravasate, never reaching the deep-seeded tumor cells, thereby limiting their efficacy. To increase tissue penetration and cellular accumulation, we propose generalizable guidelines for nanoparticle design and validate them using two different computer models that capture the potency, motion, binding kinetics, and cellular internalization of targeted nanoparticles in a section of tumor tissue. One strategy that emerged from the models was delaying nanoparticle binding until after the nanoparticles have had time to diffuse deep into the tissue. Results show that nanoparticles that are designed according to these guidelines do not require fine-tuning of their kinetics or size and can be administered in lower doses than classical targeted nanoparticles for a desired tissue penetration in a large variety of tumor scenarios. In the future, similar models could serve as a testbed to explore engineered tissue-distributions that arise when large numbers of nanoparticles interact in a tumor environment.

中文翻译：

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用于确定设计指南的计算框架，以增加靶向纳米颗粒对肿瘤的渗透


越来越多的靶向纳米颗粒被设计用于治疗癌症。通过设计，它们可以被动地积聚在肿瘤中，选择性地与其环境中的靶标结合，并提供局部治疗。然而，靶向纳米颗粒深入组织的渗透可能会因其缓慢的扩散和高结合亲和力而受到阻碍。因此，它们通常定位于血管周围的区域并从中外渗，永远不会到达深层的肿瘤细胞，从而限制了它们的功效。为了增加组织渗透和细胞积累，我们提出了纳米颗粒设计的通用指南，并使用两种不同的计算机模型对其进行验证，这些模型捕获肿瘤组织部分中靶向纳米颗粒的效力、运动、结合动力学和细胞内化。从模型中得出的一种策略是延迟纳米颗粒的结合，直到纳米颗粒有时间扩散到组织深处。结果表明，根据这些指南设计的纳米颗粒不需要对其动力学或尺寸进行微调，并且可以比传统的靶向纳米颗粒以更低的剂量施用，以在多种肿瘤情况下实现所需的组织渗透。未来，类似的模型可以作为试验台来探索当大量纳米粒子在肿瘤环境中相互作用时出现的工程组织分布。