Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study & Department of Pharmacy and Pharmacology, University of South China, Hengyang 421001, China.
State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, Gansu, China.
ACS Biomater Sci Eng. 2020 Mar 9;6(3):1565-1572. doi: 10.1021/acsbiomaterials.9b01920. Epub 2020 Feb 25.
Conjugation of various active targeting ligands to the surface of nanocarriers to realize specific recognition by the corresponding receptors localized on the membrane of the cancer cells has provided a powerful means toward enhanced cancer therapy. Folic acid (FA) is one of the most used targeting ligands due to the overexpressed FA receptors in many cancer cell lines. However, conjugation of hydrophobic FA to the surface of nanocarriers usually alters the hydrophilic/hydrophobic balance of the stabilized nanoparticles, leading to their thermodynamic instability and subsequent formation of aggregates, which apparently compromises the in vivo long circulation and minimized side effects of nanocarriers. The currently leading strategy to overcome this issue is to incorporate a protecting hydrophilic stealth that can be deshielded to expose the targeting ligand at the desired tumor site, which generally involves multistep chemical modifications, conjugations, and purifications. To develop a simple alternative toward FA-mediated enhanced anticancer drug delivery, a combination strategy of micelle complex and reducible conjugation was reported in this study. FA was first conjugated to the terminus of the hydrophilic block of a reduction-sensitive miktoarm star-shaped amphiphilic copolymer, PCL-SS-POEGMA, with the previously optimized star structure by click coupling via a reducible disulfide link. The resulting PCL-SS-POEGMA-SS-FA was further mixed with the parent PCL-SS-POEGMA to afford a micelle complex with both reducibly conjugated and relatively low amount of FA-targeting ligands toward excellent FA-mediated targeted drug delivery without compromised salt stability in vitro and in vivo. Therefore, the combined strategy developed herein provides a simple and powerful means to promote FA-mediated anticancer drug delivery.
将各种活性靶向配体缀合到纳米载体的表面，以实现对癌细胞膜上定位的相应受体的特异性识别，为增强癌症治疗提供了一种强大的手段。叶酸（FA）是最常用的靶向配体之一，因为许多癌细胞系中都过度表达了 FA 受体。然而，将疏水性 FA 缀合到纳米载体的表面通常会改变稳定的纳米粒子的亲水/亲水平衡，导致其热力学不稳定，并随后形成聚集体，这显然会损害纳米载体的体内长循环和最小化的副作用。目前克服这个问题的主要策略是引入一种保护性的亲水性隐形涂层，可以在所需的肿瘤部位解蔽以暴露靶向配体，这通常涉及多步化学修饰、缀合和纯化。为了开发一种用于 FA 介导的增强抗癌药物递送的简单替代方法，本研究报告了胶束复合物和可还原缀合的组合策略。首先，通过点击偶联将 FA 缀合到还原敏感的多臂星型两亲性嵌段共聚物 PCL-SS-POEGMA 的亲水链段末端，该星型结构通过先前优化的点击反应通过还原型二硫键连接。所得的 PCL-SS-POEGMA-SS-FA 进一步与母体 PCL-SS-POEGMA 混合，得到一种胶束复合物，其中同时含有可还原缀合的和相对低数量的 FA 靶向配体，可实现出色的 FA 介导的靶向药物递送，而不会在体外和体内牺牲盐稳定性。因此，本文开发的组合策略提供了一种简单而强大的方法来促进 FA 介导的抗癌药物递送。
