Kosaka Shunji, Fukushima Jokichi, Takeuchi Nanami, Miyamoto Noriko, de Campo Liliana, Kawano Ryuji, Nishimura Tomoki
Department of Chemistry and Materials Science, Shinshu University 3-15-1, Tokida Ueda Nagano 386-8567 Japan
Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology Tokyo 185-8588 Japan.
Chem Sci. 2025 Aug 29. doi: 10.1039/d5sc04256a.
Synthetic ion channels represent an emerging class of therapeutics. However, most synthetic ion channels are derived from small molecules, whose rapid clearance from the body limits their therapeutic potential. Here, we report macromolecular ion transport systems based on amphiphilic polyether block copolymers. The block copolymers self-assemble into vesicles that are spontaneously incorporated into biological membranes to form polymer-rich domains. The hydrophobic core of the domains, which features ether-oxygen atoms and the presence of water molecules, is analogous to the permeation pathways of natural ion channels such as KcsA. In addition, the inherent thermoresponsive properties of these polymer domains enable on/off switching of ion transport in response to temperature variations, allowing for controlled modulation of cation permeability. Thus, these domains act as macromolecular ion transport systems to disrupt ion homeostasis and trigger apoptosis in cancer cells. The systemic administration of the vesicles in tumor-bearing mice resulted in an accumulation at the tumor sites, inhibiting tumor growth. This work establishes thermoresponsive polyether block copolymers as a versatile and biologically active platform for macromolecular ion transport systems.
合成离子通道是一类新兴的治疗药物。然而，大多数合成离子通道源自小分子，其从体内的快速清除限制了它们的治疗潜力。在此，我们报道了基于两亲性聚醚嵌段共聚物的大分子离子转运系统。这些嵌段共聚物自组装成囊泡，这些囊泡会自发地整合到生物膜中形成富含聚合物的区域。这些区域的疏水核心具有醚氧原子和水分子，类似于天然离子通道（如KcsA）的渗透途径。此外，这些聚合物区域固有的热响应特性能够响应温度变化实现离子转运的开启/关闭切换，从而实现对阳离子通透性的可控调节。因此，这些区域作为大分子离子转运系统，可破坏离子稳态并触发癌细胞凋亡。在荷瘤小鼠中全身给药这些囊泡会导致其在肿瘤部位蓄积，从而抑制肿瘤生长。这项工作确立了热响应性聚醚嵌段共聚物作为大分子离子转运系统的通用且具有生物活性的平台。
