BONE TARGETED DELIVERY OF ANABOLIC AGENTS

描述(由申请人提供)： 骨质疏松症是一个主要的公共健康威胁；目前有1000万人患有骨质疏松症，估计还有3400万人由于骨量不足而面临更高的风险。2001年，全国用于骨质疏松和相关骨折的直接支出总额约为170亿美元(美国国立卫生研究院情况说明书)。提出了一种治疗骨质疏松症和其他骨骼疾病的新方法--以骨为靶向的水溶性聚合物结合物作为合成代谢剂前列腺素E_1的载体的靶向给药系统。初步的体内实验已经证明了八肽序列D-Asps作为靶向部分的潜力，可以将偶联物导向硬组织。PGEt将通过含有组织蛋白酶K敏感寡肽(Gly-Pro-NLE)和氨基苯甲醇基团的间隔基连接。该设计基于组织蛋白酶K活性部位可识别的寡肽序列结构的知识，描述了N-(2-羟丙基)甲基丙烯酰胺(HPMA)共聚物-抑制剂结合物与组织蛋白酶K活性部位的相互作用的研究，以及证明HPMA共聚物结合物通过1，6-消除释放9-氨基喜树碱的研究。初步数据表明，在被组织蛋白酶K切割后，未修饰的PGE1将通过1，6-消除而释放。释放的PGE1将在局部招募成骨细胞，促进广泛的骨形成。HPMA共聚物-(D-Asp)8-PGE1结合物将在成骨细胞和破骨细胞培养上进行体外评估。将测定它们的体内分布、最大耐受量以及对健康和去卵巢大鼠的体内治疗效果。基于活体动物数据，将建立用于治疗骨质疏松症的PGE1给药系统的设计标准。据我们所知，这是第一个适合于将合成代谢剂靶向骨骼的系统。该系统的优点是：选择性地吸附在骨转换和骨吸收速率较高的骨组织上，PGE1定位于有利于骨形成的骨骼部位，减少全身给药引起的副作用，以及设计原则适用于其他药物的输送。

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.