奥曲肽
化学
结合
药代动力学
皮下注射
药理学
体内
药物输送
生长抑素
药品
内科学
医学
有机化学
生物技术
数学分析
生物
数学
作者
Eric L. Schneider,Jeff Henise,Ralph Reid,Gary W. Ashley,Daniel V. Santi
标识
DOI:10.1021/acs.bioconjchem.6b00188
摘要
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.
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