Papademetriou Iason, Tsinas Zois, Hsu Janet, Muro Silvia
Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA.
Fischell Department of Bioengineering, University of Maryland, College Park, MD 20742, USA; Institute for Bioscience and Biotechnology Research, University of Maryland, College Park, MD 20742-4450, USA.
J Control Release. 2014 Aug 28;188:87-98. doi: 10.1016/j.jconrel.2014.06.008. Epub 2014 Jun 14.
Designing of drug nanocarriers to aid delivery of therapeutics is an expanding field that can improve medical treatments. Nanocarriers are often functionalized with elements that recognize cell-surface molecules involved in subcellular transport to improve targeting and endocytosis of therapeutics. Combination-targeting using several affinity elements further modulates this outcome. The most studied example is endothelial targeting via multiple cell adhesion molecules (CAMs), which mimics the strategy of leukocytes to adhere and traverse the vascular endothelium. Yet, the implications of this strategy on intracellular transport and in vivo biodistribution remain uncharacterized. We examined this using nanocarriers functionalized for dual- or triple-targeting to intercellular, platelet-endothelial, and/or vascular CAMs (ICAM-1, PECAM-1, VCAM-1). These molecules differ in expression level, location, pathological stimulation, and/or endocytic pathway. In endothelial cells, binding of PECAM-1/VCAM-1-targeted nanocarriers was intermediate to single-targeted counterparts and enhanced in disease-like conditions. ICAM-1/PECAM-1-targeted nanocarriers surpassed PECAM-1/VCAM-1 in control, but showed lower selectivity toward disease-like conditions. Triple-targeting resulted in binding similar to ICAM-1/PECAM-1 combination and displayed the highest selectivity in disease-like conditions. All combinations were effectively internalized by the cells, with slightly better performance when targeting receptors of different endocytic pathways. In vivo, ICAM-1/PECAM-1-targeted nanocarriers outperformed PECAM-1/VCAM-1 in control and disease-like conditions, and triple-targeted counterparts slightly enhanced this outcome in some organs. As a result, delivery of a model therapeutic cargo (acid sphingomyelinase, deficient in Niemann-Pick disease A-B) was enhanced to all affected organs by triple-targeted nanocarriers, particularly in disease-like conditions. Therefore, multi-CAM targeting may aid the optimization of some therapeutic nanocarriers, where the combination and multiplicity of the affinity moieties utilized allow modulation of targeting performance.
设计用于辅助治疗药物递送的纳米载体是一个不断发展的领域，它可以改善医学治疗。纳米载体通常用识别参与亚细胞转运的细胞表面分子的元素进行功能化，以改善治疗药物的靶向性和内吞作用。使用多种亲和元件的联合靶向进一步调节了这一结果。研究最多的例子是通过多种细胞粘附分子（CAMs）进行内皮靶向，这模仿了白细胞粘附和穿过血管内皮的策略。然而，这种策略对细胞内转运和体内生物分布的影响仍未得到充分研究。我们使用针对细胞间、血小板-内皮和/或血管CAMs（ICAM-1、PECAM-1、VCAM-1）进行双靶向或三靶向功能化的纳米载体对此进行了研究。这些分子在表达水平、位置、病理刺激和/或内吞途径方面存在差异。在内皮细胞中，靶向PECAM-1/VCAM-1的纳米载体的结合介于单靶向对应物之间，并且在疾病样条件下增强。靶向ICAM-1/PECAM-1的纳米载体在对照中超过了PECAM-1/VCAM-1，但对疾病样条件的选择性较低。三靶向导致的结合类似于ICAM-1/PECAM-1组合，并在疾病样条件下表现出最高的选择性。所有组合都能被细胞有效内化，当靶向不同内吞途径的受体时性能略好。在体内，靶向ICAM-1/PECAM-1的纳米载体在对照和疾病样条件下优于PECAM-1/VCAM-1，三靶向对应物在某些器官中略微增强了这一结果。因此，三靶向纳米载体将模型治疗货物（酸性鞘磷脂酶，尼曼-匹克病A-B缺乏）递送至所有受影响器官的能力得到增强，特别是在疾病样条件下。因此，多CAM靶向可能有助于优化一些治疗性纳米载体，其中所利用的亲和部分的组合和多样性允许调节靶向性能。
