title: Cationic and thermosensitive protamine conjugated gels for enhancing sustained human growth hormone delivery.
abstract: Thermosensitive and cationic poly(organophosphazenes) were designed and synthesized for the sustained delivery of human growth hormone (hGH) charged negatively at the physiological conditions to enhance greatly patient convenience and to improve efficacy and stability. Protamine for a complex formation with hGH was chosen and conjugated to carboxylic acid-terminated poly(organophosphazenes) by a covalent amide linkage. The aqueous solution of the cationic polymer conjugates formed a gel at 37 degrees C regardless of hGH presence. When the conjugate solution was mixed with hGH solution, a complex was formed and free hGH could be released from the complex. In the in vitro and in vivo release studies of hGH/polymer-protamine conjugate, the initial burst release was suppressed and the release period was prolonged as the protamine amount was increased. In the PK and PD studies with cynomolgus monkeys, a single administration of hGH/cationic polymer conjugate induced the elevated plasma level of hGH until 5 days and also elevated plasma level of IGF-1 as a function of free hGH until 13 days. These results suggest that the injectable, thermosensitive, and cationic poly(organophosphazene)-protamine conjugate may hold a great potential as an effective carrier for sustained release of hGH with improved patient convenience, stability and efficacy.
authors.affiliation: Division of Life Science, Korea Institute of Science and Technology, Cheongryang, Seoul 130-650, Republic of Korea.
authors.forename: Mi-Ran
authors.initials: MR
authors.lastname: Park
authors.forename: ChangJu
authors.initials: C
authors.lastname: Chun
authors.forename: Sung-Won
authors.initials: SW
authors.lastname: Ahn
authors.forename: Min-Hyo
authors.initials: MH
authors.lastname: Ki
authors.forename: Chong-Su
authors.initials: CS
authors.lastname: Cho
authors.forename: Soo-Chang
authors.initials: SC
authors.lastname: Song
mesh_terms: D000818:Animals; D002412:Cations; D004337:Drug Carriers / Q000737:chemistry*; D005782:Gels / Q000737:chemistry; D019382:Human Growth Hormone / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008422:Materials Testing; D008657:Metabolic Clearance Rate; D011479:Protamines / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013696:Temperature
chemical_list: D002412:Cations; D004337:Drug Carriers; D005782:Gels; D011479:Protamines; D019382:Human Growth Hormone