Folate Receptor-Targeted Dendrimer-Methotrexate Conjugate for Inflammatory Arthritis
Folate Receptor-Targeted Dendrimer-Methotrexate Conjugate for Inflammatory Arthritis
复制标题
叶酸受体靶向树枝状大分子-甲氨蝶呤缀合物治疗炎症性关节炎
DOI：
10.1166/jbn.2015.2077
复制
发表时间：
2015-08-01
影响因子：
2.9
通讯作者：
Baker, James R., Jr.
中科院分区：
文献类型：
--
作者：
Qi, Rong;Majoros, Istvan;Baker, James R., Jr.
第五代（G5）聚（酰氨基酰胺）（PAMAM）树枝状聚合物是已广泛用作药物递送载体的合成聚合物。甲氨蝶呤（MTX）是一种抗叶酸代谢产物，临床上已被成功地用作治疗类风湿关节炎（RA）的抗炎药物。在这项研究中，我们检查了G5 PAMAM树状聚合物甲氨蝶呤缀合物（G5-MTX）的治疗效果，该缀合物还具有与G5-MTX（G5-FA-MTX）缀合的叶酸（FA），以靶向炎症激活的叶酸受体过表达的巨噬细胞。这些细胞被认为在RA的发展中起重要作用。以G5作为对照，在RAW 264.7、NR 8383和原代大鼠腹腔巨噬细胞中评估G5-FA-MTX和G5-MTX与活化的巨噬细胞的体外结合亲和力。结果表明，任一缀合物与巨噬细胞的结合是浓度和温度依赖性的，并且可以被6.25 mM游离FA的存在阻断（p < 0.005）。G5-MTX和G5-FA-MTX偶联物对关节炎发展的预防作用在促炎剂诱导的炎性关节炎模型上进行了研究，并且在4.95 μ mol/kg的MIX等效剂量下对炎性关节炎具有相似的预防作用。这些研究表明，当多个MTX偶联在树枝状聚合物上时，它们特异性结合叶酸受体过表达的巨噬细胞，并具有与叶酸靶向MTX偶联聚合物相当的抗炎作用。
Generation 5 (G5) poly(amidoamide) (PAMAM) dendrimers are synthetic polymers that have been broadly applied as drug delivery carriers. Methotrexate (MTX), an anti-folate metabolite, has been successfully used as an anti-inflammatory drug to treat rheumatoid arthritis (RA) in the clinic. In this study, we examine the therapeutic efficacy of G5 PAMAM dendrimer methotrexate conjugates (G5-MTX) that also have folic acid (FA) conjugated to the G5-MTX (G5-FA-MTX) to target inflammation-activated folate receptors overexpressing macrophages. These cells are thought to play an important role in the development of RA. With G5 serving as a control, the in vitro binding affinities of G5-FA-MTX and G5-MTX to activated macrophages were assessed in RAW264.7, NR8383 and primary rat peritoneal macrophages. The results indicated that the binding of either conjugate to macrophages was concentration- and temperature-dependent and could be blocked by the presence of 6.25 mM free FA (p < 0.005). The preventive effects of G5-MTX and G5-FA-MTX conjugates on the development of arthritis were explored on an adjuvant-induced inflammatory arthritis model and had similar preventive effects in inflammatory arthritis at a MIX equivalent dose of 4.95 mu mol/kg. These studies indicated that when multiples of MTX are conjugated on dendritic polymers, they specifically bind to folate receptor overexpressing macrophages and have comparable anti-inflammatory effects to folate targeted MTX conjugated polymers.