Martinent Rémi, Tawffik Salman, López-Andarias Javier, Moreau Dimitri, Laurent Quentin, Matile Stefan
Department of Organic Chemistry, University of Geneva Geneva Switzerland
Chem Sci. 2021 Oct 6;12(41):13922-13929. doi: 10.1039/d1sc04828g. eCollection 2021 Oct 27.
The cytosolic delivery of various substrates in 3D multicellular spheroids by thiol-mediated uptake is reported. This is important because most orthodox systems, including polycationic cell-penetrating peptides, fail to deliver efficiently into deep tissue. The grand principles of supramolecular chemistry, that is the pH dependence of dynamic covalent disulfide exchange with known thiols on the transferrin receptor, are proposed to account for transcytosis into deep tissue, while the known but elusive exchange cascades along the same or other partners assure cytosolic delivery in kinetic competition. For quantitative detection in the cytosol, the 2D chloroalkane penetration assay (CAPA) is translated to 3D deep tissue. The targeted delivery of quantum dots, otherwise already troublesome in 2D culture, and the controlled release of mechanophores are realized to exemplify the power of thiol-mediated uptake into spheroids. As transporters, dithiolane quartets on streptavidin templates are introduced as modular motifs. Built from two amino acids only, the varied stereochemistry and peptide sequence are shown to cover maximal functional space with minimal structural change, , constitutional isomers. Reviving a classic in peptide chemistry, this templated assembly of β quartets promises to expand streptavidin biotechnology in new directions, while the discovery of general cytosolic delivery in deep tissue as an intrinsic advantage further enhances the significance and usefulness of thiol-mediated uptake.
报道了通过硫醇介导的摄取在三维多细胞球体中各种底物的胞质递送。这很重要，因为包括聚阳离子细胞穿透肽在内的大多数传统系统都无法有效地递送至深部组织。提出超分子化学的主要原理，即与转铁蛋白受体上已知硫醇的动态共价二硫键交换的pH依赖性，以解释跨细胞转运至深部组织，而沿相同或其他伙伴的已知但难以捉摸的交换级联在动力学竞争中确保胞质递送。为了在胞质溶胶中进行定量检测，将二维氯代烷渗透测定法（CAPA）转化为三维深部组织。实现了量子点的靶向递送（否则在二维培养中已经很麻烦）以及机械荧光团的控释，以例证硫醇介导的摄取进入球体的能力。作为转运体，引入了链霉亲和素模板上的二硫戊环四重奏作为模块化基序。仅由两个氨基酸构建而成，多样的立体化学和肽序列显示出以最小的结构变化覆盖最大的功能空间，即构造异构体。复兴肽化学中的经典方法，这种β四重奏的模板组装有望在新方向上扩展链霉亲和素生物技术，而在深部组织中发现一般的胞质递送作为内在优势进一步增强了硫醇介导摄取的重要性和实用性。
