Poly(d,l-lactide-co-glycolide) (PLGA)
microspheres have been used as an
injectable depot for prolonged release of
octreotide (
Sandostatin LAR®), a
peptide drug for the treatment of
acromegaly and gastrointestinal
tumors. However, acylation and incomplete release of the encapsulated
octreotide, as well as acidic degradation product-induced
inflammation are the major challenges hampering widespread clinical applications of this delivery system. The purpose of this study was to develop a novel
octreotide-delivering system utilizing naturally derived biodegradable material,
silk fibroin (SF).
Octreotide acetate was encapsulated in the SF
microspheres with a high loading (8-10 wt%) using
polyethylene glycol (PEG)-assisted emulsification method. The
octreotide-SF
microspheres exhibited a
silk I structure (low crystallinity) and burst release in in vitro release studies.
Ethanol treatment after
microsphere formation significantly increased β-sheet and
silk II structure (high crystallinity) of the
microspheres, significantly reducing the burst release and resulting in zero-order sustained release of
octreotide over 102 days, and the data could be fit to the diffusion-driven release model. After the
ethanol-treated
microspheres were intramuscularly injected into rats at low (2 mg/kg) and high (8 mg/kg)
octreotide doses, the plasma concentration of
octreotide in the high dose group remained high (>50 pg/mL) at day 28 when compared to that of the control (pure drug at low dose) and low dose
microsphere group. Interestingly, the plasma concentration for the high dose group at day 56 dramatically increased to >280 pg/mL observed at day 28. The low dose
microsphere group showed a similar increase, but at a much lower level. The rebound
octreotide level likely reflected degradation of the SF matrix which released tightly bound/trapped
octreotide. Therefore, SF
microspheres can deliver
octreotide over a long period of time with release kinetics and the mechanism different from PLGA
microsphere system.