MIP Diagnostics Ltd ., Fielding Johnson Building , Leicester , LE1 7RH United Kingdom.
Laboratory of Gene Expression and Regulation , Institute of Cytology , 194064 Saint Petersburg , Russia.
Nano Lett. 2018 Aug 8;18(8):4641-4646. doi: 10.1021/acs.nanolett.7b03206. Epub 2018 Jul 9.
Epidermal growth factor receptor (EGFR), a tyrosine kinase receptor, is over-expressed in many tumors, including almost half of triple-negative breast cancers. The latter belong to a very-aggressive and drug-resistant form of malignancy. Although humanized anti-EGFR antibodies can work efficiently against these cancers both as monotherapy and in combination with genotoxic drugs, instability and high production costs are some of their known drawbacks in clinical use. In addition, the development of antibodies to target membrane proteins is a very challenging task. Accordingly, the main focus of the present work is the design of supramolecular agents for the targeting of membrane proteins in cancer cells and, hence, more-specific drug delivery. These were produced using a novel double-imprinting approach based on the solid-phase method for preparation of molecularly imprinted polymer nanoparticles (nanoMIPs), which were loaded with doxorubicin and targeted toward a linear epitope of EGFR. Additionally, upon binding, doxorubicin-loaded anti-EGFR nanoMIPs elicited cytotoxicity and apoptosis only in those cells that over-expressed EGFR. Thus, this approach can provide a plausible alternative to conventional antibodies and sets up a new paradigm for the therapeutic application of this class of materials against clinically relevant targets. Furthermore, nanoMIPs can promote the development of cell imaging tools against difficult targets such as membrane proteins.
表皮生长因子受体（EGFR）是一种酪氨酸激酶受体，在许多肿瘤中过表达，包括近一半的三阴性乳腺癌。后者属于非常侵袭性和耐药性的恶性肿瘤。尽管人源化抗 EGFR 抗体可以作为单药治疗以及与遗传毒性药物联合使用，有效地对抗这些癌症，但在临床应用中，其不稳定性和高生产成本是已知的一些缺点。此外，针对膜蛋白的抗体的开发是一项极具挑战性的任务。因此，目前工作的主要重点是设计用于靶向癌细胞中膜蛋白的超分子试剂，从而实现更具特异性的药物递送。这些试剂是使用基于固相法的新型双重印迹方法制备的，该方法用于制备分子印迹聚合物纳米颗粒（nanoMIPs），并将其负载多柔比星并靶向 EGFR 的线性表位。此外，在结合后，负载多柔比星的抗 EGFR nanoMIPs 仅在过度表达 EGFR 的细胞中引发细胞毒性和细胞凋亡。因此，这种方法可以为传统抗体提供一种可行的替代方案，并为针对临床相关靶标的这类材料的治疗应用建立一个新的范例。此外，nanoMIPs 可以促进针对膜蛋白等困难靶标的细胞成像工具的开发。
