Polymeric micelles (PM) have been widely used as nano-sized carriers for a variety of hydrophobic drugs. Nevertheless, it has become more and more apparent that stabilization of PMs is crucial in order to prevent premature disintegration of the carrier system within the blood stream and to achieve prolonged circulation times as prerequisite for effective passive accumulation in solid tumors. Unfortunately, the majority of chemoselective cross-linking methods result in a covalent bond. Bearing bio-reversibility in mind, disulfides are an attractive option, since they provide stability in the blood stream but are reductively cleaved inside cells. Based on these considerations, we have developed a new platform for drug delivery that relies on the self-assembly of reactive poly(sarcosine)-block-poly(S-alkylsulfonyl-L-cysteine) block copolymers. These block copolymers are synthesized by amine-initiated ring-opening polymerization of α-amino acid N-carboxyanhydrides (NCAs). The newly developed S-alkylsulfonyl protective group in the hydrophobic polycysteine block enables a secondary structure-driven, controlled self-assembly into polymeric micelles (30-100 nm). The hydrophilic polysarcosine shields the active pharmaceutical ingredient (API) and allows ligand attachment on the micelle's surface. After the self-assembly of the block copolymer into micellar structures, the S-alkylsulfonyl groups of the core forming block are converted into disulfides using dithiols of different polarity, which bio-reversibly stabilizes the micelle and modules its core functionality. Depending on the cross-linker employed, the API can be physically entrapped in or covalently attached to the hydrophobic core. The latter is possible due to the high chemoselectivity of the cross-linking reaction, which enables also the use of complex lipoic acid derivatives as cross-linkers. In summary, this system uniquely allows to generate a library of functional core cross-linked carriers that can be tailored to the application in mind in a simple but controlled manner.

Core cross-linked polypept(o)ide-based nanostructures: A novel platform for drug delivery

253rd National Meeting (2017)

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