Department of Pharmacology, Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
Department of Biomedical Engineering, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
ACS Nano. 2024 Jul 2;18(26):16632-16647. doi: 10.1021/acsnano.4c00876. Epub 2024 Jun 20.
While local nanoparticle delivery to lymph nodes is well studied, there are few design criteria for intravenous delivery to the entire lymph node repertoire. In this study, we investigated the effect of NP pH transition on lymph node targeting by employing a series of ultra-pH-sensitive (UPS) polymeric micelles. The UPS library responds to pH thresholds (p 6.9, 6.2, and 5.3) over a range of physiological pH. We observed a dependence of intravenous lymph node targeting on micelle pH transition. UPS (subscript indicates p) shows poor lymph node delivery, while UPS delivers efficiently to lymph node sets. We investigated targeting mechanisms of UPS, observing an accumulation among lymph node lymphatics and a dependence on lymph node-resident macrophages. To overcome the pH-threshold barrier, which limits UPS, we rationally designed a nanoparticle coassembly of UPS with UPS, called HyUPS. The HyUPS micelle retains the constitutive pH transitions of each polymer, showing stepwise responses to discrete pH thresholds. We demonstrate that HyUPS improves UPS delivery to lymph nodes, extending this platform for disease detection of lymph node metastasis.
虽然局部纳米颗粒递送至淋巴结的研究已有很多，但静脉内递送至整个淋巴结库的设计标准却很少。在这项研究中，我们通过一系列超 pH 敏感（UPS）聚合物胶束研究了 NP pH 转变对淋巴结靶向的影响。UPS 库在一系列生理 pH 值范围内响应 pH 阈值（p 6.9、6.2 和 5.3）。我们观察到静脉内淋巴结靶向与胶束 pH 转变之间存在依赖性。UPS（下标表示 p）显示出对淋巴结的递送效果不佳，而 UPS 则有效地递送至淋巴结集落。我们研究了 UPS 的靶向机制，观察到在淋巴结淋巴管中积累，并依赖于淋巴结驻留的巨噬细胞。为了克服限制 UPS 的 pH 阈值障碍，我们合理设计了 UPS 与 UPS 的纳米粒子共组装，称为 HyUPS。HyUPS 胶束保留了每种聚合物的组成型 pH 转变，对离散的 pH 阈值表现出逐步响应。我们证明 HyUPS 改善了 UPS 向淋巴结的递送，扩展了该平台用于淋巴结转移疾病的检测。
