Wong Pamela T, Choi Seok Ki
Department of Internal Medicine, Michigan Nanotechnology Institute for Medicine and Biological Sciences, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Int J Mol Sci. 2015 Jan 13;16(1):1772-90. doi: 10.3390/ijms16011772.
The rational design of a nanoplatform in drug delivery plays a crucial role in determining its targeting specificity and efficacy in vivo. A conventional approach relies on the surface conjugation of a nanometer-sized particle with two functionally distinct types of molecules, one as a targeting ligand, and the other as a therapeutic agent to be delivered to the diseased cell. However, an alternative simplified approach can be used, in which a single type of molecule displaying dual function as both a targeting ligand and therapeutic agent is conjugated to the nanoparticle. In this review, we evaluate the validity of this new strategy by using methotrexate, which displays multifunctional mechanisms of action. Methotrexate binds to the folate receptor, a surface biomarker frequently overexpressed in tumor cells, and also inhibits dihydrofolate reductase, an enzyme critical for cell survival and division. Thus we describe a series of fifth generation poly(amido amine) dendrimers conjugated with methotrexate, and discuss several lines of evidence supporting the efficacy of this new platform strategy based on surface plasmon resonance spectroscopy, enzyme activity assays, and cell-based studies with folate receptor (+) KB cancer cells.
纳米平台在药物递送中的合理设计对于确定其体内靶向特异性和疗效起着关键作用。传统方法依赖于将纳米级颗粒与两种功能不同的分子进行表面偶联，一种作为靶向配体，另一种作为要递送至患病细胞的治疗剂。然而，可以采用另一种简化方法，即将具有靶向配体和治疗剂双重功能的单一类型分子偶联到纳米颗粒上。在本综述中，我们通过使用具有多种作用机制的甲氨蝶呤来评估这种新策略的有效性。甲氨蝶呤与叶酸受体结合，叶酸受体是肿瘤细胞中经常过度表达的一种表面生物标志物，并且还抑制二氢叶酸还原酶，这是一种对细胞存活和分裂至关重要的酶。因此，我们描述了一系列与甲氨蝶呤偶联的第五代聚（酰胺胺）树枝状大分子，并基于表面等离子体共振光谱、酶活性测定以及对叶酸受体（+）KB癌细胞的细胞研究，讨论了支持这种新平台策略有效性的几条证据。
