BONE TARGETED DELIVERY OF ANABOLIC AGENTS

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DESCRIPTION (provided by applicant): Osteoporosis is a major public health threat; 10 million individuals are currently afflicted with the disease and an estimated 34 million more are at increased risk due to low bone mass. Total national direct expenditures for osteoporotic and associated fractures were approximately $17 billion in 2001 (NIH Fact Sheets). A new approach for the treatment of osteoporosis and other skeletal diseases is proposed - a targeted drug delivery system employing bone-targeted, water-soluble polymer conjugates as a carrier for the anabolic agent, prostaglandin, PGE1. Preliminary in vivo experiments have demonstrated the potential of the octapeptide sequence D-Asps as a targeting moiety to vector a conjugate towards hard tissues. PGEt will be attached via a spacer that contains a cathepsin K-sensitive oligopeptide (Gly-Pro-Nle) and an aminobenzylalcohol group. The design is based on the knowledge of oligopeptide sequences structures recognizable by the active site of cathepsin K, studies that described the interaction of N-(2- hydroxypropyl)methacrylamide (HPMA) copolymer - inhibitor conjugates with the active site of cathepsin K, and studies that demonstrated that HPMA copolymer conjugates release 9-aminocamptothecin by 1,6- elimination. Preliminary data indicates that, following cleavage by cathepsin K, unmodified PGE1 will be released by 1,6-elimination. The released PGE1 will act locally to recruit osteoblasts and promote extensive bone formation. HPMA copolymer - (D-Asp)8 - PGE1 conjugates will be evaluated in vitro on osteoblast and osteoclast cell cultures. Their body distribution, maximum tolerated dose, and in vivo therapeutic effect on healthy and ovariectomized rats will be determined. Based on in vivo animal data, criteria will be established for the design of a PGE1 delivery system for the treatment of osteoporosis. To our knowledge, this is the first system suitable for targeting an anabolic agent to bone. The advantages of the proposed system are: selective adsorption to the tissues in bone with higher rates of bone turnover and resorption, localization of PGE1 in skeletal sites where bone formation would be beneficial, the reduction of side-effects resulting from the systemic administration of PGE, and applicability of design principles to the delivery of other drugs.