Water-soluble HPMA copolymer-prostaglandin E1 conjugates containing a cathepsin K sensitive spacer

• Published in: Journal of drug targeting Vol. 14; no. 6; pp. 425 - 435
• Main Authors: Pan, Huaizhong, Kope ková, Pavla, Wang, Dong, Yang, Jiyuan, Miller, Scott, Kope ek, Jind ich
• Format: Journal Article
• Language: English
• Published: Abington Informa UK Ltd 01.07.2006; Taylor & Francis
• Subjects: Acrylamides - chemistry; Alprostadil - administration & dosage; Alprostadil - chemistry; Alprostadil - pharmacokinetics; Biological and medical sciences; Cathepsin K; cathepsin K sensitive spacer; Cathepsins - chemistry; Cathepsins - genetics; Cathepsins - metabolism; Chromatography, High Pressure Liquid; Drug Delivery Systems - methods; Fluorescence; General pharmacology; HPMA; Humans; Hydrophobic and Hydrophilic Interactions; Medical sciences; Molecular Structure; Molecular Weight; Osteoporosis; PGE; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; polymer-prostaglandin conjugates; Polymers - chemistry; Solubility; Spectrophotometry, Ultraviolet; Technology, Pharmaceutical - methods; Water - chemistry; cathepsin K sensitive spacer; Cathepsin K; Pharmaceutical technology; Enzyme; Cysteine endopeptidases; PGE1; Diseases of the osteoarticular system; polymer-prostaglandin conjugates; Polymer; Prostaglandin E1; Carboxypeptidase C; Serine-type carboxypeptidases; Peptidases; Water soluble compound; Methacrylamide derivative copolymer; Osteoporosis; Spacer; Water solubility; Hydrolases; Conjugated compound; HPMA
• ISSN: 1061-186X; 1029-2330
• DOI: 10.1080/10611860600834219

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.