Poly(S-Alkylsulfonyl-L-Cysteine) in Modular Nanoparticle Synthesis : exploring key factors from disulfide stabilization, polypept(o)ide architectures to secondary structures
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Abstract
RNA interference (RNAi) enables the silencing of gene expression demonstrating enormous clinical potential. Systemic application of RNAi therapeutics, however, requires delivery strategies evading enzymatic degradation in combination with stability in blood for long systemic circulation. This thesis comprises the consecutive development of polypept(o)ide-based core-shell carrier systems to fulfill this task.
Polypept(o)ides show great promise as a synthetic delivery platform in medical application and allow for a controlled synthesis of well-defined materials with conformational and chemical diversity. The presented work closes a relevant synthetic gap in polymerization of these materials with the development of S-alkylsulfonyl-L-cysteines. The established novel protective and activating group for thiols, for the first time, mediates direct chemoselective disulfide formation in compatibility with the nucleophilic ring-opening polymerization strategy. (Multi)block copolypept(o)ides with orthogonal thiol reactivity could thus be sequentially polymerized and were implemented in secondary structure-modulated self-assembly of cross-linked nanoparticles with control over size, morphology as well as functionality. In vivo application of the resulting cationic systems revealed outstandingly stable blood circulation in combination with passive tumor accumulation and a low systemic burden. Eventually, RNAi mediated knockdown in solid tumors was realized upon systemic delivery by cationic, cross-linked polypept(o)ide-based systems, concluding this journey towards gene delivery vectors in systemic application.