Sampogna-Mireles Diana, Araya-Durán Ingrid D, Márquez-Miranda Valeria, Valencia-Gallegos Jesús A, González-Nilo Fernando D
Centro de Biotecnología FEMSA, Escuela de Ingeniería y Ciencias, Tecnológico de Monterrey, Av. Eugenio Garza Sada 2501 Sur, Col. Tecnológico, Monterrey, N.L, Mexico.
Universidad Andres Bello, Center for Bioinformatics and Integrative Biology (CBIB), Facultad de Ciencias Biológicas, Av. República 239, Santiago, Chile.
J Mol Graph Model. 2017 Mar;72:201-208. doi: 10.1016/j.jmgm.2017.01.004. Epub 2017 Jan 6.
Dendrimers functionalized with folic acid (FA) are drug delivery systems that can selectively target cancer cells with folate receptors (FR-α) overexpression. Incorporation of polyethylene glycol (PEG) can enhance dendrimers solubility and pharmacokinetics, but ligand-receptor binding must not be affected. In this work we characterized, at atomic level, the binding functionality of conventional site-specific dendrimers conjugated with FA with PEG 750 or PEG 3350 as a linker. After Molecular Dynamics simulation, we observed that both PEG's did not interfere over ligand-receptor binding functionality. Although binding kinetics could be notably affected, the folate fragment from both dendrimers remained exposed to the solvent before approaching selectively to FR-α. PEG 3350 provided better solubility and protection from enzymatic degradation to the dendrimer than PEG 750. Also, FA-PEG3350 dendrimer showed a slightly better interaction with FR-α than FA-PEG750 dendrimer. Therefore, theoretical evidence supports that both dendrimers are suitable as drug delivery systems for cancer therapies.
用叶酸（FA）功能化的树枝状大分子是一种药物递送系统，它可以选择性地靶向过度表达叶酸受体（FR-α）的癌细胞。聚乙二醇（PEG）的加入可以提高树枝状大分子的溶解度和药代动力学，但不能影响配体-受体的结合。在这项工作中，我们在原子水平上表征了以PEG 750或PEG 3350作为连接体与FA共轭的传统位点特异性树枝状大分子的结合功能。经过分子动力学模拟，我们观察到两种PEG均未干扰配体-受体的结合功能。尽管结合动力学可能会受到显著影响，但两种树枝状大分子的叶酸片段在选择性接近FR-α之前仍暴露于溶剂中。与PEG 750相比，PEG 3350为树枝状大分子提供了更好的溶解度和对酶降解的保护。此外，FA-PEG3350树枝状大分子与FR-α的相互作用略优于FA-PEG750树枝状大分子。因此，理论证据支持这两种树枝状大分子都适合作为癌症治疗的药物递送系统。
