By using a 4-dimethylaminopyridine (DMAP) catalysed reaction of β-hydroxyamino acid derivatives with tertbutyl pyrocarbonate [(Boc) 2 O], dehydroamino acid derivatives are obtained in high yields. The same methodology applied to dipeptides with a β-hydroxyamino acid residue gives the corresponding dipeptides with a dehydroamino acid residue.

Gold nanoparticles functionalized with Gd(3+) chelates displaying fast water exchange, superb pH stability and inertness towards transmetalation with Zn(2+) have been prepared and characterized as a new high relaxivity (29 mM(-1) s(-1), 30 MHz, 25 °C) contrast agent potentially safe for in vivo MRI applications. The Lipari-Szabo treatment for internal rotation was used to evaluate the effect of linker flexibility on the relaxivity of the gold nanoparticles. The effect of fast water exchange on the relaxivity of gold nanoparticles functionalized with Gd(3+) chelates is also addressed in this communication.

In this work, we introduce dipeptides containing tryptophan N-capped with the nonsteroidal anti-inflammatory drug naproxen and C-terminal dehydroamino acids, dehydrophenylalanine (ΔPhe), dehydroaminobutyric acid (ΔAbu), and dehydroalanine (ΔAla) as efficacious protease resistant hydrogelators. Optimized conditions for gel formation are reported. Transmission electron microscopy experiments revealed that the hydrogels consist of networks of micro/nanosized fibers formed by peptide self-assembly. Fluorescence and circular dichroism spectroscopy indicate that the self-assembly process is driven by stacking interactions of the aromatic groups. The naphthalene groups of the naproxen moieties are highly organized in the fibers through chiral stacking. Rheological experiments demonstrated that the most hydrophobic peptide (containing C-terminal ΔPhe) formed more elastic gels at lower critical gelation concentrations. This gel revealed irreversible breakup, while the C-terminal ΔAbu and ΔAla gels, although less elastic, exhibited structural recovery and partial healing of the elastic properties. A potential antitumor thieno[3,2-b]pyridine derivative was incorporated (noncovalently) into the gel formed by the hydrogelator containing C-terminal ΔPhe residue. Fluorescence and Förster resonance energy transfer measurements indicate that the drug is located in a hydrophobic environment, near/associated with the peptide fibers, establishing this type of hydrogel as a good drug-nanocarrier candidate.

Self-assembled peptide hydrogels have emerged in recent years as the new paradigm in biomaterials research. We have contributed to this field the development of hydrogels based on dehydrodipeptides N-capped with naproxen. The dehydrodipeptide hydrogels can be loaded with drugs, thus being potential nanocarriers for drug delivery. In this work novel dehydrodipeptides containing tyrosine and aspartic acid amino acid residues N-capped with naproxen and C-terminal dehydrophenylalanine were prepared and characterized. Superparamagnetic iron oxide nanoparticles (SPIONs) were incorporated into the dehydrodipeptide-based hydrogels and their effect on the self-assembly, structure and rheological and magnetic properties of the hydrogels was studied. Magnetic hydrogels, with incorporated SPIONs, displayed concentration-dependent T2-MRI contrast enhancement. Moreover, upon magnetic excitation (alternating magnetic field –AMF–) the SPIONs were able to generate a significant amount of heat. Hence, magnetic hyperthermia can be used as a remote trigger for release of drug cargos and SPIONs incorporated into the self-assembled dehydrodipeptide hydrogels.

Supramolecular hydrogels rely on small molecules that self-assemble in water as a result of the cooperative effect of several relatively weak intermolecular interactions. Peptide-based low molecular weight hydrogelators have attracted enormous interest owing to the simplicity of small molecules combined with the versatility and biocompatibility of peptides. In this work, naproxen, a well known non-steroidal anti-inflammatory drug, was N-conjugated with various dehydrodipeptides to give aromatic peptide amphiphiles that resist proteolysis. Molecular dynamic simulations were used to obtain insight into the underlying molecular mechanism of self-assembly and to rationalize the design of this type of hydrogelators. The results obtained were in excellent agreement with the experimental observations. Only dehydrodipeptides having at least one aromatic amino acid gave hydrogels. The characterization of the hydrogels was carried out using transmission electron microscopy (TEM), circular dichroism (CD), fluorescence spectroscopy and also rheological assays. Results and discussion SynthesisFive new dehydrodipeptides N-protected with naproxen (Npx) were prepared from the corresponding methyl esters of N-tertbutoxycarbonyl-β-hydroxydipeptides. The strategy deployed involved a dehydration reaction followed by cleavage of the tert-butoxycarbonyl group (Boc), reaction with (S)-(+)naproxen chloride and alkaline hydrolysis of the methyl esters (Scheme 1). The dehydroamino acids used were dehydrophenylalanine (∆Phe) and dehydroaminobutyric acid (∆Abu). This synthetic methodology was chosen to avoid racemization issues concerning the naproxen moiety. The N,Cdiprotected dipeptides having a β-hydroxyamino acid (Scheme 1, 1a-e) were dehydrated in good to high yields by treatment with tert-butyldicarbonate (Boc 2 O) and 4dimethylaminopyridine (DMAP) followed by N,N,N',N'tetramethylguanidine (TMG) 17 (Scheme 1, 2a-e). The Boc group was removed with trifluoroacetic acid (TFA) (Scheme 1, 3a-e) and the N-deprotected dehydrodipeptides were conjugated with (S)-(+)-naproxen (Scheme 1, 4a-e). Finally, the methyl esters were removed by treatment with a solution of NaOH (1 M) affording compounds 5a-e in good yields (Scheme 1).