Non-coding double-stranded RNAs, including small interfering RNA (siRNA), can act as regulatory key factors after gene transcription by specific, base sequence-mediated silencing of messenger RNAs (mRNA) in a mechanism named RNA interference (RNAi) and thus, offer great therapeutic potential. For systemic application of siRNA a delivery system is necessary to protect it from clearance or degradation and transport it to the site of action. Therefore, the delivery system needs to provide intrinsic stability and shielding for prolonged blood circulation to enable accumulation in e.g. solid tumors and further reversible encapsulation to release the siRNA after reaching its target.

Polypeptide-block-polypeptoid copolymers (polypept(o)ides) represent a promising new class of material, as they combine biodegradability, biocompatibility and stability in aqueous media with intrinsic multi-functionality and the ability of self-assembly, modulated by secondary structures formation. The polypeptoid poly(sarcosine) (pSar), which is commonly used in our group, is one of the most promising alternatives to replace the gold standard PEG as shielding material for nanodimensional delivery systems. Polymers can be synthesized by nucleophilic-initiated ring-opening polymerization (ROP) of the corresponding α-amino acid N-carboxyanhydrides (NCAs) which allows precise control over block length or sequence.

The aim of the project is the development of polypept(o)ide-based delivery systems to use siRNA as systemic applicated therapeutic agent against e.g. solid tumors. First developments are based on triblock copolymer structures consisting of cationic poly(l-lysine) (pLys) for efficient siRNA complexation, poly(l-S-ethylsulfonyl-cysteine) (pCys(SO₂Et)) block for chemoselective disulfide cross-linking and poly(sarcosine) (pSar) to mediate stealth-like properties.

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