title: Subcutaneously Administered Self-Cleaving Hydrogel-Octreotide Conjugates Provide Very Long-Acting Octreotide.
abstract: 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-Phe(1) or the ε-amine of Lys(5) 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.
authors.affiliation: ProLynx , 455 Mission Bay Boulevard South, Suite 145, San Francisco, California 94158, United States.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Schneider
authors.affiliation: ProLynx , 455 Mission Bay Boulevard South, Suite 145, San Francisco, California 94158, United States.
authors.forename: Jeff
authors.initials: J
authors.lastname: Henise
authors.affiliation: ProLynx , 455 Mission Bay Boulevard South, Suite 145, San Francisco, California 94158, United States.
authors.forename: Ralph
authors.initials: R
authors.lastname: Reid
authors.affiliation: ProLynx , 455 Mission Bay Boulevard South, Suite 145, San Francisco, California 94158, United States.
authors.forename: Gary W
authors.initials: GW
authors.lastname: Ashley
authors.affiliation: ProLynx , 455 Mission Bay Boulevard South, Suite 145, San Francisco, California 94158, United States.|Department of Pharmaceutical Chemistry, University of California, San Francisco , 600 16th Street, San Francisco, California 94158, United States.
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Santi
mesh_terms: D000818:Animals; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry*; D020100:Hydrogels / Q000737:chemistry*; D007279:Injections, Subcutaneous; D008863:Microspheres; D015282:Octreotide / Q000008:administration & dosage* / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D020100:Hydrogels; D011092:Polyethylene Glycols; D015282:Octreotide