Department of Biomedical Engineering, Yale University, New Haven, CT, US.
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, US.
Nat Commun. 2024 May 18;15(1):4247. doi: 10.1038/s41467-024-48442-7.
The in vivo efficacy of polymeric nanoparticles (NPs) is dependent on their pharmacokinetics, including time in circulation and tissue tropism. Here we explore the structure-function relationships guiding physiological fate of a library of poly(amine-co-ester) (PACE) NPs with different compositions and surface properties. We find that circulation half-life as well as tissue and cell-type tropism is dependent on polymer chemistry, vehicle characteristics, dosing, and strategic co-administration of distribution modifiers, suggesting that physiological fate can be optimized by adjusting these parameters. Our high-throughput quantitative microscopy-based platform to measure the concentration of nanomedicines in the blood combined with detailed biodistribution assessments and pharmacokinetic modeling provides valuable insight into the dynamic in vivo behavior of these polymer NPs. Our results suggest that PACE NPs-and perhaps other NPs-can be designed with tunable properties to achieve desired tissue tropism for the in vivo delivery of nucleic acid therapeutics. These findings can guide the rational design of more effective nucleic acid delivery vehicles for in vivo applications.
聚合物纳米粒子（NPs）的体内疗效取决于其药代动力学，包括循环时间和组织趋向性。在这里，我们探索了一套由不同组成和表面性质的聚（胺-酯）（PACE）NPs 组成的文库，以指导其生理命运的结构-功能关系。我们发现，循环半衰期以及组织和细胞类型趋向性取决于聚合物化学、载体特性、给药剂量以及分布调节剂的策略性联合使用，这表明通过调整这些参数可以优化生理命运。我们基于高通量定量显微镜的平台来测量血液中纳米药物的浓度，结合详细的生物分布评估和药代动力学建模，为这些聚合物 NPs 的动态体内行为提供了有价值的见解。我们的结果表明，PACE NPs-也许还有其他 NPs-可以通过可调的特性来设计，以实现体内递送核酸治疗药物的理想组织趋向性。这些发现可以为体内应用指导更有效的核酸递送载体的合理设计。
