Fine-tuning Nanocarriers Specifically toward Cargo: A Competitive Study on Solubilizing Related Photosensitizers for Photodynamic Therapy

Abstract

Tailor-made drug solubilizers are studied based on peptide-poly(ethylene glycol) conjugates, which exhibit peptide segments constituting binding motifs for the small-molecule drugs of interest to render them water-soluble. Suitable 7mer peptides are selected via combinatorial means by screening large one-bead-one-compound (OBOC) peptide libraries. The capability of the screening method to read out structural detail of the drugs is investigated by comparing three related photosensitizers (Chlorin E6 (Ce6), Pheophorbide A (Pba) and meta-tetra(hydroxyphenyl)chlorin (m-THPC), which are applicable for photodynamic cancer therapy. The screening procedure delivers de novo solubilizers that show the best solubilization efficiency for the drug the screening is performed with. While molecular recognition events between peptide and drug are not expected to be found, significant binding capacity differences of, e.g., the Ce6-solubilizer for Pba are suggesting selectivity in drug binding, even among structurally closely related drugs. Cyro-Electron microscopy revealed the formation of colloidal aggregates between drug moieties and peptide conjugates. Insights into relevant amino acids in the identified peptide sequences are gained by studying capacities of systematic point mutations (alanine scans), enabling understanding of drug-binding motifs. These reveal the importance of sequence positioning of appropriate H-bonding between polar functional groups of the peptide and the drugs, which agrees well with computational binding studies performed on drug/peptide model complexes.

Gaining Insights into Specific Drug Formulation Additives for Solubilizing a Potential Anti‐Alzheimer Disease Drug B4A1

“…Resulting peptide‐PEG conjugates could reach in some cases payload capacities of close to 1:1 drug to carrier. A remarkable correlation of the drug structures and the oligopeptide sequence was observed in a recent study on solubilization of structurally related photosensitizers, indicating drug‐specific interactions despite the small length of the peptide 7mer segments …”

“…Recently, peptide‐polymer conjugates proved to constitute a versatile platform to address biomedical applications from switchable bioactive surfaces to fibrillar materials as extracellular matrix surrogates, to additives for distinct plasmid DNA compactization for potential gene delivery applications or material specific antifouling coatings . Particularly the combination of poly(ethylene glycol) (PEG) and oligopeptide segments leads to a versatile platform of formulation additives, where interactions to a drug could be fine‐tuned, resulting in sequence‐specific solubilization or even transport systems . Peptide‐PEG conjugates could render a large scope of problematic small molecule drugs water‐soluble.…”

Von Peptiden lernen: eine Strategie für das Design funktionaler Präzisionspolymer‐Sequenzen

“…[13] Die Sequenzanalyse mithilfe einer systematischen Alaninsubstitution (Ala-Scan) zeigte die hohe Bedeutung des FFLFF-Segments fürd ie Wirkstoffbeladung,d ai nd iesem Bereich ein Aminosäureaustausch gegen Alanin zu drastisch reduzierten Beladungen führte.Der Austausch der terminalen Gln1-bzw.Gln7-Reste durch Alanin erhçhte die Beladung hingegen um 14 %b zw. Das Konjugat wurde tiefergehend analysiert, um die sequenzspezifischen Beiträge zu den Beladungs-und Freisetzungseigenschaften zu verstehen.…”

“…Das Konjugat wurde tiefergehend analysiert, um die sequenzspezifischen Beiträge zu den Beladungs-und Freisetzungseigenschaften zu verstehen. [13] Die Sequenzanalyse mithilfe einer systematischen Alaninsubstitution (Ala-Scan) zeigte die hohe Bedeutung des FFLFF-Segments fürd ie Wirkstoffbeladung,d ai nd iesem Bereich ein Aminosäureaustausch gegen Alanin zu drastisch reduzierten Beladungen führte.Der Austausch der terminalen Gln1-bzw.Gln7-Reste durch Alanin erhçhte die Beladung hingegen um 14 %b zw. 39 %.…”

“…39 %. [13] Weiterhin konnte die Bedeutung von Leu4 fürd ie Beladung gezeigt werden. Hierzu wurden zwei Peptid-PEG-Konjugate synthetisiert, bei denen der Ersatz von Leu4 durch Va lbzw.Ala zu einer deutlichen Reduktion der Beladbarkeit um 58 %b zw.9 2% führte (Hintergrundinformationen (S.I.)…”