School of Pharmacy, University of East Anglia, Norwich Research Park, NR4 7TJ, UK.
Cardiff School of Pharmacy & Pharmaceutical Sciences, Redwood Building, Cardiff, CF10 3NB, UK.
Pharm Res. 2017 Dec;34(12):2517-2531. doi: 10.1007/s11095-017-2190-7. Epub 2017 Jun 14.
Polyamidoamine (PAMAM) dendrimers are a promising class of nanocarrier with applications in both small and large molecule drug delivery. Here we report a comprehensive evaluation of the uptake and transport pathways that contribute to the lung disposition of dendrimers.
Anionic PAMAM dendrimers and control dextran probes were applied to an isolated perfused rat lung (IPRL) model and lung epithelial monolayers. Endocytosis pathways were examined in primary alveolar epithelial cultures by confocal microscopy. Molecular interactions of dendrimers with protein and lipid lung fluid components were studied using small angle neutron scattering (SANS).
Dendrimers were absorbed across the intact lung via a passive, size-dependent transport pathway at rates slower than dextrans of similar molecular sizes. SANS investigations of concentration-dependent PAMAM transport in the IPRL confirmed no aggregation of PAMAMs with either albumin or dipalmitoylphosphatidylcholine lung lining fluid components. Distinct endocytic compartments were identified within primary alveolar epithelial cells and their functionality in the rapid uptake of fluorescent dendrimers and model macromolecular probes was confirmed by co-localisation studies.
PAMAM dendrimers display favourable lung biocompatibility but modest lung to blood absorption kinetics. These data support the investigation of dendrimer-based carriers for controlled-release drug delivery to the deep lung.
聚酰胺-胺（PAMAM）树枝状大分子是一类很有前途的纳米载体，可应用于小分子和大分子药物的递送。本研究全面评估了促进树枝状大分子向肺部分布的摄取和转运途径。
将阴离子 PAMAM 树枝状大分子和对照葡聚糖探针应用于离体灌流大鼠肺（IPRL）模型和肺上皮细胞单层。通过共聚焦显微镜检查原代肺泡上皮细胞中的内吞途径。使用小角中子散射（SANS）研究树枝状大分子与蛋白质和肺液脂质成分的分子相互作用。
树枝状大分子通过完整肺的被动、尺寸依赖性转运途径以比类似分子大小的葡聚糖慢的速率被吸收。在 IPRL 中进行的 PAMAM 浓度依赖性转运的 SANS 研究证实，PAMAMs 与白蛋白或二棕榈酰磷脂酰胆碱肺衬里液成分没有聚集。在原代肺泡上皮细胞中鉴定了不同的内吞隔室，并通过共定位研究证实了其在荧光树枝状大分子和模型大分子探针快速摄取中的功能。
PAMAM 树枝状大分子显示出良好的肺生物相容性，但肺到血液的吸收动力学较差。这些数据支持基于树枝状大分子的载体用于向深部肺部的控释药物递送的研究。
