Control of octreotide release from silk fibroin microspheres

He Gong; Jing Wang; Jue Zhang; Jianbing Wu; Zhaozhu Zheng; Xusheng Xie; David L Kaplan; Gang Li; Xiaoqin Wang

doi:10.1016/j.msec.2019.05.004

Control of octreotide release from silk fibroin microspheres

Mater Sci Eng C Mater Biol Appl. 2019 Sep:102:820-828. doi: 10.1016/j.msec.2019.05.004. Epub 2019 May 3.

Authors

He Gong¹, Jing Wang², Jue Zhang¹, Jianbing Wu¹, Zhaozhu Zheng¹, Xusheng Xie¹, David L Kaplan³, Gang Li⁴, Xiaoqin Wang⁵

Affiliations

¹ National Engineering Laboratory for Modern Silk, College of Textile and Clothing Engineering, Soochow University, Suzhou 215123, China.
² Laboratory Animal Center of Soochow University, Suzhou, China 215123.
³ Department of Biomedical Engineering, 4 Colby Street, Tufts University, Medford, MA 02155, USA.
⁴ National Engineering Laboratory for Modern Silk, College of Textile and Clothing Engineering, Soochow University, Suzhou 215123, China. Electronic address: tcligang@suda.edu.cn.
⁵ National Engineering Laboratory for Modern Silk, College of Textile and Clothing Engineering, Soochow University, Suzhou 215123, China. Electronic address: wangxiaoqin@suda.edu.cn.

PMID: 31147054
DOI: 10.1016/j.msec.2019.05.004

Abstract

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.

Keywords: Controlled release; Fibroin; Microsphere; Octreotide; Silk.

MeSH terms

Animals
Bombyx
Drug Liberation*
Ethanol / chemistry
Female
Fibroins / chemistry*
Methanol / chemistry
Microspheres*
Octreotide / blood
Octreotide / pharmacokinetics*
Particle Size
Rats, Sprague-Dawley

Substances

Ethanol
Fibroins
Octreotide
Methanol