Enhanced Gene Delivery Triggered by Dual pH/Redox Responsive Host-Guest Dimerization of Cyclooligosaccharide Star Polycations

Description

A robust strategy is reported to build perfectly monodisperse star polycationscombining a trehalose-based cyclooligosaccharide (cyclotrehalan, CT) centralcore onto which oligoethyleneimine radial arms are installed. Thearchitectural perfection of the compounds is demonstrated by a variety ofphysicochemical techniques, including NMR, MS, DLS, TEM, and GPC. Key tothe strategy is the possibility of customizing the cavity size of the macrocyclicplatform to enable/prevent the inclusion of adamantane motifs. Theseproperties can be taken into advantage to implement sequential levels ofstimuli responsiveness by combining computational design, precisionchemistry and programmed host-guest interactions. Specifically, it is shownthat supramolecular dimers implying a trimeric CT-tetraethyleneimine starpolycation and purposely designed bis-adamantane guests are preorganizedto efficiently complex plasmid DNA (pDNA) into transfection-competentnanocomplexes. The stability of the dimer species is responsive to theprotonation state of the cationic clusters, resulting in dissociation at acidicpH. This process facilitates endosomal escape, but reassembling can takeplace in the cytosol then handicapping pDNA nuclear import. By equippingthe ditopic guest with a redox-sensitive disulfide group, recapturingphenomena are prevented, resulting in drastically improved transfectionefficiencies both in vivo and in vitro.

Abstract

Ministerio de Ciencia e Innovación y Agencia Estatal de Investigación, de España-MCIN/AEI/10.13039/501100011033

Abstract

Fondo Europeo de Desarrollo Regional de la Unión Europea-RTI2018-097609-B-C21, RTI2018-097609-B-C22, PID2019-105858RB-I00 y PID2020-118384GB-I00

Abstract

Junta de Andalucía-P20_00166

Additional details