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Enhanced Gene Delivery Triggered by Dual pH/Redox Responsive Host‐Guest Dimerization of Cyclooligosaccharide Star Polycations
Author(s) -
CarbajoGordillo Ana I.,
LópezFernández José,
Benito Juan M.,
Jiménez Blanco José L.,
SantanaArmas María L.,
Marcelo Gema,
Di Giorgio Christophe,
Przybylski Cédric,
Ortiz Mellet Carmen,
Tros de Ilarduya Conchita,
Mendicuti Francisco,
García Fernández José M.
Publication year - 2022
Publication title -
macromolecular rapid communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.348
H-Index - 154
eISSN - 1521-3927
pISSN - 1022-1336
DOI - 10.1002/marc.202200145
Subject(s) - adamantane , supramolecular chemistry , chemistry , protonation , cationic polymerization , gene delivery , combinatorial chemistry , dispersity , redox , transfection , biophysics , polymer chemistry , molecule , organic chemistry , biochemistry , ion , biology , gene
Abstract A robust strategy is reported to build perfectly monodisperse star polycations combining a trehalose‐based cyclooligosaccharide (cyclotrehalan, CT) central core onto which oligoethyleneimine radial arms are installed. The architectural perfection of the compounds is demonstrated by a variety of physicochemical techniques, including NMR, MS, DLS, TEM, and GPC. Key to the strategy is the possibility of customizing the cavity size of the macrocyclic platform to enable/prevent the inclusion of adamantane motifs. These properties can be taken into advantage to implement sequential levels of stimuli responsiveness by combining computational design, precision chemistry and programmed host‐guest interactions. Specifically, it is shown that supramolecular dimers implying a trimeric CT‐tetraethyleneimine star polycation and purposely designed bis‐adamantane guests are preorganized to efficiently complex plasmid DNA (pDNA) into transfection‐competent nanocomplexes. The stability of the dimer species is responsive to the protonation state of the cationic clusters, resulting in dissociation at acidic pH. This process facilitates endosomal escape, but reassembling can take place in the cytosol then handicapping pDNA nuclear import. By equipping the ditopic guest with a redox‐sensitive disulfide group, recapturing phenomena are prevented, resulting in drastically improved transfection efficiencies both in vivo and in vitro.