Subcutaneously Administered Self-Cleaving Hydrogel–Octreotide Conjugates Provide Very Long-Acting Octreotide
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- 作者：Eric L. Schneider ; Jeff Henise ; Ralph Reid ; Gary W. Ashley ; Daniel V. Santi
- 刊名：Bioconjugate Chemistry
- 出版年：2016
- 出版时间：July 20, 2016
- 年：2016
- 卷：27
- 期：7
- 页码：1638-1644
- 全文大小：336K
- 年卷期：0
- ISSN：1520-4812
文摘
We developed a long-acting drug-delivery system that supports subcutaneous administration of the peptidic somatostatin agonist octreotide—a blockbuster drug used to treat acromegaly and neuroendocrine tumors. The current once-a-month polymer-encapsulated octreotide, Sandostatin LAR, requires a painful intragluteal injection through a large needle by a health-care professional. To overcome such shortcomings, Tetra-PEG hydrogel microspheres were covalently attached to the α-amine of d-Phe1 or the ε-amine of Lys5 of octreotide by a self-cleaving β-eliminative linker; upon subcutaneous injection in the rat using a small-bore needle, octreotide was slowly released. The released drug from the ε-octreotide conjugate showed a remarkably long serum half-life that exceeded two months. The α-octreotide conjugate had a half-life of ∼2 weeks, and showed an excellent correlation of in vitro and in vivo drug release. Pharmacokinetic models indicate these microspheres should support once-weekly to once-monthly self-administered subcutaneous dosing in humans. The hydrogel–octreotide conjugate shows the favorable pharmacokinetics of Sandostatin LAR without its drawbacks.