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

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.