Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne 3052, Australia.
ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne 3052, Australia.
Mol Pharm. 2020 Aug 3;17(8):2938-2951. doi: 10.1021/acs.molpharmaceut.0c00348. Epub 2020 Jul 13.
Interstitial administration (e.g., subcutaneous (SC) administration) of immunotherapies and vaccines within nanoparticles can improve access to lymph-resident immune cells, leading to enhanced efficacy and reduced off-target effects. Recently, endogenous high-density lipoproteins (HDLs) were found to return from peripheral tissue back to the systemic circulation via the lymphatic vessels and nodes. This suggests the potential utility of HDLs as biocompatible lymphatic-targeted therapeutic carriers. However, we have a limited understanding of the mechanisms that drive HDL uptake into peripheral lymphatics from the interstitium. This study investigated the influence of HDL physicochemical properties on lymphatic transport and lymph node (LN) retention of HDL after SC administration. A range of HDL particles was prepared and characterized. Sphere-shaped endogenous HDLs were isolated from biological fluids (rat lymph, rat plasma, and human plasma) and separated into two subclasses based on the density. Discoidal-shaped synthetic (reconstituted) HDLs (rHDLs) of similar sizes were assembled from lipids and apolipoprotein A-I. All HDLs had similar sizes of 10-20 nm and a slightly negative surface charge. All HDLs were radiolabeled with H-cholesteryl ester (H-CE) and/or C-free cholesterol (C FC) and administered SC into the hind leg of thoracic lymph-cannulated rats. The recovery of radiolabels in lymph, plasma, LN, and tissues was determined. From the interstitial injection site, all HDLs were preferentially transported into the lymph and not blood vessels as indicated by high lymph-to-plasma concentration ratios of the radiolabels (up to 100:1 during the absorption phase) and greater radiolabel recovery in LNs draining the injection site compared to the contralateral side. Several HDLs with unique composition demonstrated significantly higher lymphatic transport compared to other HDLs despite possessing similar physical properties, suggesting that HDL lymphatic transport is less influenced by physical properties. The LN retention of HDL was positively correlated to increasing the negative charge of HDL, which was related to surface composition. Overall, this study informs the optimal design of HDL-based nanoparticles to promote lymphatic targeting of immunotherapies and vaccines.
间质给药（例如，皮下（SC）给药）可以将免疫疗法和疫苗递送至纳米颗粒内，从而改善对驻留于淋巴组织中的免疫细胞的接触，增强疗效并减少脱靶效应。最近，人们发现内源性高密度脂蛋白（HDL）可以通过淋巴管和淋巴结从外周组织返回全身循环。这表明 HDL 作为生物相容的淋巴靶向治疗载体具有潜在的应用价值。然而，我们对 HDL 从间质摄取进入外周淋巴管的机制知之甚少。本研究调查了 HDL 物理化学性质对 SC 给药后 HDL 向淋巴系统转运和淋巴结（LN）保留的影响。制备并表征了一系列 HDL 颗粒。从生物流体（大鼠淋巴、大鼠血浆和人血浆）中分离出球形内源性 HDL，并根据密度将其分为两个亚类。由脂质和载脂蛋白 A-I 组装而成的盘形合成（重组）HDL（rHDL）具有相似的大小。所有 HDL 的大小均为 10-20nm，表面带轻微负电荷。所有 HDL 均用 H-胆固醇酯（H-CE）和/或 C 无胆固醇（C FC）放射性标记，并通过 SC 给药至胸部淋巴插管大鼠的后腿。测定放射性标记物在淋巴、血浆、LN 和组织中的回收情况。从间质注射部位，所有 HDL 都优先进入淋巴管而不是血管，这表明放射性标记物的淋巴/血浆浓度比值很高（吸收阶段高达 100:1），并且与对侧相比，注射部位引流的 LN 中回收的放射性标记物更多。尽管具有相似的物理性质，但几种具有独特组成的 HDL 显示出明显更高的淋巴转运，这表明 HDL 淋巴转运受物理性质的影响较小。HDL 的 LN 保留与 HDL 带电量的增加呈正相关，这与表面组成有关。总的来说，这项研究为基于 HDL 的纳米颗粒的最佳设计提供了信息，以促进免疫疗法和疫苗的淋巴靶向。
