Abstract
PURPOSE: Macromolecular delivery systems have therapeutic uses because of their ability to deliver and release drugs to specific tissues. The uptake and localization of HPMA copolymers using Asp(8) as the bone-targeting moiety was determined in aged, ovariectomized (ovx) rats. PGE(1) was attached via a cathepsin K-sensitive linkage to HPMA copolymer-Asp(8) conjugate and was tested to determine if it could promote bone formation. MATERIALS AND METHODS: The uptake of FITC-labeled HPMA copolymer-Asp(8) conjugate (P-Asp(8)-FITC) on bone surfaces was compared with the mineralization marker, tetracycline. Then a targeted PGE(1)-HPMA copolymer conjugate (P-Asp(8)-FITC-PGE(1)) was given as a single injection and its effects on bone formation were measured 4 weeks later. RESULTS: P-Asp(8)-FITC preferentially deposited on resorption surfaces, unlike tetracycline. A single injection of P-Asp(8)-FITC-PGE(1) resulted in greater indices of bone formation in aged, ovx rats. CONCLUSIONS: HPMA copolymers can be targeted to bone surfaces using Asp(8), with preferential uptake on resorption surfaces. Additionally, PGE(1) attached to the Asp(8)-targeted HPMA copolymers and given by a single injection resulted in greater bone formation measured 4 weeks later. This initial in vivo study suggests that macromolecular delivery systems targeted to bone may offer some therapeutic opportunities and advantages for the treatment of skeletal diseases.