College of Engineering and Science - Chemistry, Louisiana Tech University , Ruston, Louisiana 71272, United States.
Institute for Drug Discovery, Purdue University , West Lafayette, Indiana 47907, United States.
Biomacromolecules. 2017 Oct 9;18(10):3082-3088. doi: 10.1021/acs.biomac.7b00728. Epub 2017 Sep 14.
Folate-receptor-positive activated macrophages are critical for the development and maintenance of many chronic inflammatory and autoimmune diseases. Previously, small-molecule folate-targeted conjugates were found to specifically bind to these activated macrophages in vitro and selectively accumulate at sites of inflammation in vivo. While these small-molecule conjugates have shown promise, the use of a folate-targeted, higher cargo capacity nanovehicle may prove superior in delivering imaging or therapeutic agents in vivo. This nanoparticle strategy has been demonstrated in oncology, where targeted dendrimers have shown superior delivery capabilities; however, little research has been pursued in the area of folate-targeted dendrimers for inflammation and autoimmune diseases. Therefore, we endeavored to create a folate-decorated dendrimer to explore its uptake in mouse models of ulcerative colitis and atherosclerosis. We demonstrate that our final poly(ethylene glycol)-coated, acetic-anhydride-capped, folate-targeted poly(amidoamine) dendrimer exhibits no discernible cytotoxicity in vitro, specifically binds to a folate-receptor-expressing macrophage cell line in vitro, and selectively accumulates in areas of inflammation in vivo.
叶酸受体阳性激活的巨噬细胞对于许多慢性炎症和自身免疫性疾病的发生和维持至关重要。此前发现，小分子叶酸靶向缀合物在体外特异性结合这些激活的巨噬细胞，并在体内炎症部位选择性积累。虽然这些小分子缀合物显示出了一定的前景，但使用叶酸靶向、更高载药能力的纳米载体可能在体内递送成像或治疗剂方面更具优势。这种纳米颗粒策略在肿瘤学中已经得到了验证，其中靶向树突状聚合物已显示出优越的递药能力；然而，在炎症和自身免疫性疾病的叶酸靶向树突状聚合物领域的研究甚少。因此，我们致力于构建一种叶酸修饰的树突状聚合物，以探索其在溃疡性结肠炎和动脉粥样硬化小鼠模型中的摄取情况。我们证明，我们最终的聚乙二醇（PEG）包覆、醋酸酐封端、叶酸靶向聚酰胺-胺（PAMAM）树突状聚合物在体外没有明显的细胞毒性，在体外特异性结合表达叶酸受体的巨噬细胞系，并在体内炎症部位选择性积累。
