Sequence positioning of disulfide linkages to program the degradation of monodisperse poly(amidoamines)

A polymer drug-carrier was synthesized by combining a monodisperse, sequence-defined poly(amidoamine) segment with a poly(ethylene oxide)-block (PAA-block-PEO). Between both polymer blocks a single disulfide moiety is incorporated that allows for the realization of a programmed disassembly of the carrier polymer in a reductive environment, like for instance present in certain intracellular compartments. The sequence selective positioning is realized using cystamine as a new building block for the automated synthesis of monodisperse PAAs. The controlled disassembly of the polymeric carrier was used to establish a two-phase release process, e.g., highly relevant for an effective release after successful drug delivery into a cell. The applicability of this carrier was demonstrated by analyzing the complexation behavior of the system with plasmid DNA, before and after reductive degradation of the block copolymer. The presented observations describe a transition in polyplex (polymer-DNA complex) properties from PEO-stabilized ion complexes with soft charge compensation to compact structures with more effective charge neutralization after cleavage of the PEO-block.