title: Water-soluble HPMA copolymer--prostaglandin E1 conjugates containing a cathepsin K sensitive spacer.
abstract: A novel bone targeting, N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer based, prostaglandin E1 (PGE1) delivery system was designed, synthesized and characterized. PGE1 was bound to the polymer backbone via a spacer, composed of a cathepsin K sensitive tetrapeptide (Gly-Gly-Pro-Nle) and a self-eliminating 4-aminobenzyl alcohol structure. The HPMA copolymer conjugates were prepared by photo-initiated free radical copolymerization of HPMA, PGE1-containing macromonomer, and optionally a comonomer containing a reactive p-nitrophenyl ester group. The latter group was used as attachment points for the D-aspartic acid octapeptide targeting moieties. Incubation of the PGE1-containing macromonomer and HPMA copolymer-PGE1 conjugates with cathepsin K resulted in release of unmodified PGE1. The rate of release depended on the composition of the conjugate. The higher the PGE1 content in the conjugate, the slower the PGE1 release. This appeared to be the result of association of hydrophobic side-chains in aqueous media, which rendered the formation of the enzyme substrate complex more difficult. The data seems to indicate that HPMA copolymer-PGE1 conjugates have a potential in the treatment of osteoporosis and other bone diseases.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT 84112-5820, USA.
authors.forename: Huaizhong
authors.initials: H
authors.lastname: Pan
authors.forename: Pavla
authors.initials: P
authors.lastname: Kopecková
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.forename: Jiyuan
authors.initials: J
authors.lastname: Yang
authors.forename: Scott
authors.initials: S
authors.lastname: Miller
authors.forename: Jindrich
authors.initials: J
authors.lastname: Kopecek
mesh_terms: D000178:Acrylamides / Q000737:chemistry*; D000527:Alprostadil / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D056657:Cathepsin K; D002403:Cathepsins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems / Q000379:methods*; D005453:Fluorescence; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D015394:Molecular Structure; D008970:Molecular Weight; D011108:Polymers / Q000737:chemistry; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013678:Technology, Pharmaceutical / Q000379:methods; D014867:Water / Q000737:chemistry
chemical_list: D000178:Acrylamides; D011108:Polymers; D014867:Water; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; D000527:Alprostadil; C032976:N-(2-hydroxypropyl)methacrylamide