Charge-altering releasable transporters, or CARTs, are block cooligomers with a lipophilic block and a cationic block. They are synthesized via organocatalytic ring-opening polymerization with controlled numbers of cationic monomer units that rearrange and degrade at physiological pH to form neutral products. Their structure and degradation profile make CARTs effective at complexing and transfecting therapeutic anionic nucleic acids like messenger RNA (mRNA), and releasing them inside the cell to be translated into proteins. They are also relatively unique from a fundamental standpoint because they are lipophilic-cationic block cooligomers instead of the hydrophilic-cationic block copolymers that are commonly used, and the presence of the lipophilic block is required for successful delivery. CART/mRNA complexes were previously shown to efficiently induce expression of different mRNAs in both cultured cells and animals, but their fundamental physical structure has yet to be determined. Small-angle neutron scattering, light scattering, and cryogenic transmission electron microscopy results will be shown that characterize the solution structure of the CART molecules and CART/nucleic acid complexes. As a comparison, nondegradable CART analogues are also studied and serve as model systems without the added complexity of pH sensitivity.

Solution structure of lipophilic-charged block cooligomers and complexes for delivering therapeutic nucleic acids

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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