Design and in vitro validation of multivalent dendrimer methotrexates as a folate-targeting anticancer therapeutic.
Design and in vitro validation of multivalent dendrimer methotrexates as a folate-targeting anticancer therapeutic.
复制标题
DOI：
10.2174/1381612811319370004
复制
发表时间：
2013
影响因子：
3.1
通讯作者：
Choi SK
中科院分区：
文献类型：
--
作者：
Thomas TP;Joice M;Sumit M;Silpe JE;Kotlyar A;Bharathi S;Kukowska-Latallo J;Baker JR;Choi SK
癌症靶向纳米疗法的设计依赖于一对两个功能正交的分子，一个作为癌细胞特异性靶向配体，另一个作为治疗性细胞毒性剂。本研究研究了另一种简化策略的有效性，其中具有靶向和细胞毒活性的双重作用分子与纳米颗粒缀合作为癌症靶向纳米治疗剂。在此，我们证明甲氨蝶呤适用于这种双重作用策略，因为它与作为肿瘤生物标志物的叶酸受体（FAR）具有合理的亲和力，并且具有胞质二氢叶酸还原酶的细胞毒性抑制活性。本文介绍了新型甲氨蝶呤缀合的聚酰胺胺 (PAMAM) 树枝状聚合物的设计，每个树枝状聚合物均携带通过稳定的酰胺接头连接的多个甲氨蝶呤副本。我们通过在 FAR 过表达细胞中进行表面等离子共振光谱、无细胞酶测定和基于细胞的实验来评估它们的双重生物活性。这项研究将最佳连接框架和多价性的组合确定为有助于实现有效双重活性的两个关键设计元素。
Design of cancer-targeting nanotherapeutics relies on a pair of two functionally orthogonal molecules, one serving as a cancer cell-specific targeting ligand, and the other as a therapeutic cytotoxic agent. The present study investigates the validity of an alternative simplified strategy where a dual-acting molecule which bears both targeting and cytotoxic activity is conjugated to the nanoparticle as cancer-targeting nanotherapeutics. Herein we demonstrate that methotrexate is applicable for this dual-acting strategy due to its reasonable affinity to folic acid receptor (FAR) as a tumor biomarker, and cytotoxic inhibitory activity of cytosolic dihydrofolate reductase. This article describes design of new methotrexate-conjugated poly(amidoamine) (PAMAM) dendrimers, each carrying multiple copies of methotrexate attached through a stable amide linker. We evaluated their dual biological activities by performing surface plasmon resonance spectroscopy, a cell-free enzyme assay and cell-based experiments in FAR-overexpressing cells. This study identifies the combination of an optimal linker framework and multivalency as the two key design elements that contribute to achieving potent dual activity.