Combinatorial Screening for Specific Drug Solubilizers with Switchable Release Profiles

Polymer‐block‐peptide conjugates are tailored to render hydrophobic small molecule drugs water soluble. The combinatorial strategy selects for bioconjugates that exhibit sequence‐specific solubilization and switchable release profiles of the cargo through incorporation of a disulfide linker moiety into the peptide‐library design. While the study focused on the photosensitizer m‐THPC and reductive carrier cleavage, the approach is generic and might be expanded toward a broad range of poorly soluble small‐molecule drugs and other selective cleavage mechanisms to disassemble a peptide binding domain of the bioconjugate‐based solubilizer. Tailored peptide–PEO‐conjugates with switchable drug release profiles for solubilization of water‐insoluble small‐molecule drugs are selected by screening a combinatorial split and mix peptide library. A disulfide backbone linker moiety, cleavable in reductive environments, is incorporated in the peptide library for triggered releases of the cargo molecule. Drug payload, aggregate size, and drug activation kinetics are fine‐tunable though changes in the carrier amino acid sequence.