Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139.
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139.
Proc Natl Acad Sci U S A. 2021 Oct 19;118(42). doi: 10.1073/pnas.2104826118.
Nanoparticle (NP) stiffness has been shown to significantly impact circulation time and biodistribution in anticancer drug delivery. In particular, the relationship between particle stiffness and tumor accumulation and penetration in vivo is an important phenomenon to consider in optimizing NP-mediated tumor delivery. Layer-by-layer (LbL) NPs represent a promising class of multifunctional nanoscale drug delivery carriers. However, there has been no demonstration of the versatility of LbL systems in coating systems with different stiffnesses, and little is known about the potential role of LbL NP stiffness in modulating in vivo particle trafficking, although NP modulus has been recently studied for its impact on pharmacokinetics. LbL nanotechnology enables NPs to be functionalized with uniform coatings possessing molecular tumor-targeting properties, independent of the NP core stiffness. Here, we report that the stiffness of LbL NPs is directly influenced by the mechanical properties of its underlying liposomal core, enabling the modulation and optimization of LbL NP stiffness while preserving LbL NP outer layer tumor-targeting and stealth properties. We demonstrate that the stiffness of LbL NPs has a direct impact on NP pharmacokinetics, organ and tumor accumulation, and tumor penetration-with compliant LbL NPs having longer elimination half-life, higher tumor accumulation, and higher tumor penetration. Our findings underscore the importance of NP stiffness as a design parameter in enhancing the delivery of LbL NP formulations.
纳米颗粒 (NP) 的刚性已被证明会显著影响抗癌药物输送中的循环时间和生物分布。特别是，颗粒刚性与体内肿瘤积累和穿透的关系是优化 NP 介导的肿瘤输送中需要考虑的一个重要现象。层层 (LbL) NPs 是一类很有前途的多功能纳米级药物输送载体。然而，还没有证明 LbL 系统在具有不同刚性的涂层系统中的多功能性，并且对于 LbL NP 刚性在调节体内颗粒迁移中的潜在作用知之甚少，尽管 NP 模量最近因其对药代动力学的影响而被研究。LbL 纳米技术使 NPs 能够通过具有分子肿瘤靶向特性的均匀涂层进行功能化，而与 NP 核的刚性无关。在这里，我们报告说，LbL NPs 的刚性直接受到其底层脂质体核的机械性能的影响，从而能够在保持 LbL NP 外层肿瘤靶向和隐身特性的同时调节和优化 LbL NP 的刚性。我们证明了 LbL NPs 的刚性对 NP 药代动力学、器官和肿瘤积累以及肿瘤穿透有直接影响——顺应性 LbL NPs 的消除半衰期更长、肿瘤积累更高、肿瘤穿透更深。我们的研究结果强调了 NP 刚性作为增强 LbL NP 制剂递送的设计参数的重要性。
