Abstract
Traditional approaches to achieve sustained delivery of pharmaceutical peptides traditionally use co-excipients (e.g., microspheres and hydrogels). Here, we investigate the release of an amyloidogenic glucagon analogue (3474) from an aggregated state and the influence of surfactants on this process. The formulation of peptide 3474 in dodecyl maltoside (DDM), rhamnolipid (RL), and sophorolipid (SL) led to faster fibrillation. When the aggregates were subjected to multiple cycles of release by repeated resuspension in fresh buffer, the kinetics of the release of soluble peptide 3474 from different surfactant aggregates all followed a simple exponential decay fit, with half-lives of 5–18 min and relatively constant levels of release in each cycle. However, different amounts of peptide are released from different aggregates, ranging from 0.015 mg/mL (3475-buffer) up to 0.03 mg/mL (3474-DDM), with 3474-buffer and 3474-RL in between. In addition to higher release levels, 3474-DDM aggregates showed a different amyloid FTIR structure, compared to 3474-RL and 3474-SL aggregates and a faster rate of degradation by proteinase K. This demonstrates that the stability of organized peptide aggregates can be modulated to achieve differences in release of soluble peptides, thus coupling aggregate polymorphism to differential release profiles. We achieved aggregate polymorphism by the addition of different surfactants, but polymorphism may also be reached through other approaches, including different excipients as well as changes in pH and salinity, providing a versatile handle to control release profiles.
Highlights
The controlled release of pharmaceutical drugs is subject to intense research efforts
Amyloid formation occurs above the equilibrium solubility of the monomeric species and is usually detected with the dye thioflavin T, which undergoes a marked increase in fluorescence upon binding fibrils [18]
Chemicals: Rhamnolipid (RL), 90% pure, was from Agae Technologies (Corvallis, OR), 87% pure sophorolipid was from Ecover (Malle, Belgium), dodecyl maltoside (DDM) came from Avanti Lipids (Alabaster, AL), proteinase K was from MP Biomedicals (Santa Ana, CA), and all other chemicals were from Sigma
Summary
The controlled release of pharmaceutical drugs is subject to intense research efforts. A good example is provided by insulin degludec, in which the natural propensity of insulin to form fibers consisting of concatemers of hexameric subunits with zinc is exploited for sustained release of insulin over 42 h [12] Another way to assemble proteins is via amyloid aggregates, i.e., cross β-sheet fiber aggregates formed by proteins and peptides [13]. Amyloids may offer a general approach to depot formation Their high resistance to proteolysis, pH changes, physical stress, and chemical stability [24,25,26,27] offer the prospect of a common strategy for the release of peptides and unstructured proteins. Most short-acting variants did not form amyloids
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