A computational framework for identifying design guidelines to increase the penetration of targeted nanoparticles into tumors.
A computational framework for identifying design guidelines to increase the penetration of targeted nanoparticles into tumors.
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DOI：
10.1016/j.nantod.2013.11.001
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发表时间：
2013-12-01
期刊：
影响因子：
17.4
通讯作者：
Bhatia SN
中科院分区：
文献类型：
--
作者：
Hauert S;Berman S;Nagpal R;Bhatia SN
靶向纳米颗粒越来越多地被设计用于治疗癌症。通过设计，它们可以被动地在肿瘤中积累，选择性地与环境中的目标结合，并提供局部治疗。然而，目标纳米颗粒渗透到组织深处可能会受到其缓慢扩散和高结合亲和力的阻碍。因此，它们通常局限于血管周围的外渗区域，从未到达深层肿瘤细胞，从而限制了它们的疗效。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来验证它们，这些模型可以捕获肿瘤组织切片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大小进行微调，并且可以以比传统靶向纳米颗粒更低的剂量施用，以达到在各种肿瘤情况下所需的组织穿透。在未来，类似的模型可以作为一个实验平台来探索当大量纳米颗粒在肿瘤环境中相互作用时产生的工程组织分布。
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.