Arginine end-functionalized poly(l-lysine) dendrigrafts for the stabilization and controlled release of insulin

Insulin complexes with PEGylated basic oligopeptides

“…This conversion increases the number of available insulin interacting sites with oligopeptide derivatives, and this promotes further aggregation of nanoparticles to larger particles. The same behavior was also reported in interaction studies between the arginine end-functionalized derivatives of a poly(L-lysine) dendrigraft having various numbers of guanidinium end-groups [17]. Similar sizes were also reported upon insulin interaction with positively charged polymers [16,21,31,34].…”

“…The structure of OLys-PEG750 and OLys-PEG2000 was established by proton and carbon NMR spectroscopy. The previously prepared PEGylated oligo(L-lysines) and the parent OLys were fully functionalized with eight guanidinium endgroups by a method analogous to one previously reported [17,29], affording two PEGylated oligoarginine-type derivatives, OArg-PEG750 and OArg-PEG2000. In brief, to 0.05 mmol of OLys or of PEGylated oligo(L-lysine) derivatives dissolved in dry DMF (10 mL), a DMF solution (10 mL) containing 0.50 mmol 1H-pyrazole-1-carboxamidine hydrochloride and 0.50 mmol N,N-diisopropylethylamine was added dropwise, and the solution was allowed to react for 24 h under argon atmosphere.…”

“…NUV-CD spectroscopy was used to study the proposed [17] dissociation of insulin dimers upon interaction with the oligopeptide derivatives as a function of oligopeptide/insulin molar ratio. Insulin dimers and hexamers exhibit a characteristic tyrosyl CD signal at $275 nm.…”

“…Several approaches have been employed in order to realize an effective insulin oral formulation. These include the application of absorption enhancers [8], protease inhibitors [9], and cell penetrating peptides [10] or the attachment of poly(ethylene glycol) chains to insulin [11] and the use of drug delivery systems such as liposomes [12], nanoparticles [13,14], hydrogels [15], or polymers that spontaneously form nanocomplexes with insulin in aqueous environment [16,17]. Protein delivery systems relying on complexation and assembly of proteins with linear or branched polymers present an alternative interesting approach.…”

“…In this case, although the interaction results in the formation of aggregates, insulin absorption is improved due to disaggregation taking place in the presence of intestinal degradation enzymes. Based on these results, guanidinium end-functionalized derivatives of a poly(L-lysine) dendrigraft having various numbers of arginine end-groups have been prepared [17]. These guanidinylated derivatives spontaneously and efficiently interact electrostatically with insulin affording dendrigraft/insulin complexes.…”