Feasibility of using a bone-targeted, macromolecular delivery system coupled with prostaglandin E₁ to promote bone formation in aged, estrogen-deficient rats

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 Asp₈ as the bone-targeting moiety was determined in aged, ovariectomized (ovx) rats. PGE₁ was attached via a cathepsin K-sensitive linkage to HPMA copolymer-Asp₈ conjugate and was tested to determine if it could promote bone formation. Materials and Methods. The uptake of FITC-labeled HPMA copolymer-Asp₈ conjugate (P-Asp₈-FITC) on bone surfaces was compared with the mineralization marker, tetracycline. Then a targeted PGE₁-HPMA copolymer conjugate (P-Asp₈-FITC-PGE₁) was given as a single injection and its effects on bone formation were measured 4 weeks later. Results. P-Asp₈-FITC preferentially deposited on resorption surfaces, unlike tetracycline. A single injection of P-Asp₈-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, PGE₁ attached to the Asp₈-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.