BackgroundPeptide-drug-conjugates (PDCs) are being developed as an effective strategy to specifically deliver cytotoxic drugs to cancer cells. However one of the challenges to their successful application is the relatively low stability of peptides in the blood, liver and kidneys. Since AuNPs seem to have a longer plasma half-life than PDCs, one approach to overcoming this problem would be to conjugate the PDCs to gold nanoparticles (AuNPs), as these have demonstrated favorable physico-chemical and safety properties for drug delivery systems. We set out to test whether PEG coated-AuNPs could provide a suitable platform for the non-covalent loading of pre-formed PDCs and whether this modification would affect the bioavailability of the PDCs and their cytotoxicity toward target cancer cells.MethodsPeptides specifically internalized by A20 murine lymphoma cells were isolated from a phage library displaying 7mer linear peptides. Peptide specificity was validated by flow cytometry and confocal microscopy. PDCs were synthesized containing a selected peptide (P4) and either chlorambucil (Chlor), melphalan (Melph) or bendamustine (Bend). Gold nanoparticles were sequentially coated with citrate, PEG-6000 and then PDC (PDC-PEG-AuNP). The physico-chemical properties of the coated particles were analyzed by electrophoresis, TEM, UV–VIS and FTIR. Stability of free and PDC-coated AuNP was determined.ResultsBiopanning of the phage library resulted in discovery of several novel peptides that internalized into A20 cells. One of these (P4) was used to synthesize PDCs containing either Chlor, Melph or Bend. All three PDCs specifically killed A20 target cells, however they had short half-lives ranging from 10.6 to 15.4 min. When coated to PEG-AuNPs, the half-lives were extended to 21.0–22.3 h. The PDC-PEG-AuNPs retained cytotoxicity towards the target cells. Moreover, whereas pre-incubation for 24 h of free PDCs almost completely abolished their cytotoxic activity, the PDC-PEG-AuNPs were still active even after 72 h pre-incubation.ConclusionsPeptide-drug-conjugates hold potential for improving the target efficacy of chemotherapeutic drugs, however their short half-lives may limit their application. This hurdle can be overcome by easily conjugating them to gold nanoparticles. This conjugation also opens up the possibility of developing slow release formulations of targeted drug delivery systems containing PDCs.Electronic supplementary materialThe online version of this article (10.1186/s12951-018-0362-1) contains supplementary material, which is available to authorized users.

Amino acid and peptide couplings are widely used in fields related to pharma and materials. Still, current peptide synthesis continues to rely on the use of expensive, water sensitive, and waste‐generating coupling reagents, which are often prepared in multi‐step sequences and used in excess. Herein is described a peptide coupling reaction design that relies mechanistically on sun‐light activation of a 4‐dimethylamino‐pyridine–alkyl halide charge‐transfer complex to generate a novel coupling reagent in situ. The resulting coupling method is rapid, does not require dry solvents or inert atmosphere, and is compatible with all the most common amino acids and protecting groups. Peptide couplings can be run on gram‐scale, without the use of special equipment. This method has a significantly reduced environmental and financial footprint compared to standard peptide coupling reactions. Experimental and computational studies support the proposed mechanism.

Amino acid and peptide couplings are widely used in fields related to pharma and materials. Still, current peptide synthesis continues to rely on the use of expensive, water sensitive, and waste‐generating coupling reagents, which are often prepared in multi‐step sequences and used in excess. Herein is described a peptide coupling reaction design that relies mechanistically on sun‐light activation of a 4‐dimethylamino‐pyridine–alkyl halide charge‐transfer complex to generate a novel coupling reagent in situ. The resulting coupling method is rapid, does not require dry solvents or inert atmosphere, and is compatible with all the most common amino acids and protecting groups. Peptide couplings can be run on gram‐scale, without the use of special equipment. This method has a significantly reduced environmental and financial footprint compared to standard peptide coupling reactions. Experimental and computational studies support the proposed mechanism.

No abstract

No abstract