BONE TARGETED DELIVERY OF ANABOLIC AGENTS

合成代谢药物的骨靶向输送

• 批准号: 7663959
• 负责人: JINDRICH H. KOPECEK
• 金额: $ 30.1万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7663959
• 关键词: Abbreviations; Acetylene; Active Sites; Address; Adriamycin PFS; Adsorption; Adverse effects; Alcohols; Alendronate; Alprostadil; Anabolic Agents; Animal Model; Animals; Binding; Biodistribution; Biological; Biomechanics; Blood Circulation; Bond-It; Bone Density; Bone Mineral Contents; Bone Resorption; Bone Tissue; Carbon; Cell surface; Characteristics; Chemistry; Cleaved cell; D-Aspartic Acid; Data; Development; Dose; Doxorubicin; Drug Carriers; Drug Controls; Drug Delivery Systems; Dual-Energy X-Ray Absorptiometry; Enzyme Immunoassay; Enzymes; Esters; Ethers; Evaluation; Fluorescein; Fluorescein-5-isothiocyanate; Fluoresceins; Gene Expression; Genes; Goals; Hormone replacement therapy; Human; Hydrolysis; Hydroxyapatites; In Vitro; Injection of therapeutic agent; Isothiocyanates; Kidney; Kinetics; Label; Length; Leu-Gly; Ligands; Link; Macrophage Colony-Stimulating Factor; Maximum Tolerated Dose; Mediating; Medical; Metabolism; Minerals; Modeling; Modification; Molecular Profiling; Molecular Weight; Mus; Musculoskeletal Diseases; Nuclear; Oligopeptides; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Parathyroid Hormones; Peptides; Peripheral; Permeability; Pharmaceutical Preparations; Plasma; Polymers; Population; Postmenopausal Osteoporosis; Prodrugs; Property; Prostaglandins; Prostaglandins E; Protocols documentation; Public Health; Rattus; Reaction; Research; Rodent; Route; Selective Estrogen Receptor Modulators; Series; Side; Site; Skeleton; Structure; Sulfhydryl Compounds; Surface; System; TNFSF11 gene; Testing; Therapeutic; Therapeutic Agents; Thiones; Time; Tissues; Treatment Protocols; Urethane; Validation; Vertebral column; Water; Woman; X-Ray Computed Tomography; age group; aged; azobis(isobutyronitrile); base; bone; bone cell; bone turnover; cathepsin K; copolymer; cost; deoxypyridinoline; design; efficacy evaluation; glomerular filtration; glycylphenylalanine; human PTH protein; human WFDC2 protein; improved; in vivo; indexing; macromolecule; men; methacrylamide; mortality; new technology; novel; novel strategies; osteogenic; phenylalanylleucine; polymerization; progesterone 11-hemisuccinate-(2-iodohistamine); prolyl-glycyl-glycine; protein aminoacid sequence; public health relevance; pyridine; receptor; research study; skeletal; skeletal disorder; skeletal tissue; targeted delivery; tartrate-resistant acid phosphatase; therapeutic evaluation; trafficking; trithiocarbonate

DESCRIPTION (provided by applicant): Osteoporosis is a major public health threat. Currently, osteoporosis is present in an estimated 44 million men and women aged 50 and older, which represent 55 percent of the population in that age group in the USA. In addition to the enormous medical costs, this condition leads to a substantial increase in mortality. A new approach for the treatment of osteoporosis and other musculoskeletal diseases is proposed a targeted drug delivery system employing bone targeted; water-soluble polymer conjugates as carriers for the anabolic agent, prostaglandin E1. Previous experiments have demonstrated that D-Asp8-targeted conjugates are preferentially incorporated onto bone resorption surfaces. This offers a unique opportunity to target drugs to sites of active bone resorption. Another encouraging result was the observation that increases in bone formation could be sustained for at least a month following a single injection of the conjugate. The main aim of the proposed research is to design novel, effective conjugates for the treatment of osteoporosis. We designed new, biodegradable N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates. An important design characteristic is the insertion of degradable bonds into the polymer main chain (backbone). Consequently, a higher molecular weight than with nondegradable carriers may be used, resulting in long circulation times and enhanced accumulation in bone due to leaky vasculature and increased number of targeting moieties per chain. Main features of the new design are as follows: a) The new biodegradable HPMA-based polymeric carrier will be composed of short telechelic HPMA copolymer segments, containing PGE1 and targeting moieties, prepared by RAFT (reversible addition-fragmentation chain transfer) polymerization using an azido-functionalized RAFT chain transfer agent. These segments will be extended into high molecular weight (long-circulating) carriers by a highly efficient click chemistry reaction with enzymatically degradable (acetylene functionalized) oligopeptides; b) The targeting D-Asp8 group will be bound to the polymer backbone via a cathepsin K sensitive spacer; c) PGE1 will be bound to the polymer backbone via an ether bond; it will be connected to the carrier via an 1,6-elimination group and a cathepsin K sensitive spacer. The previously used ester bond was stable in humans, but susceptible to hydrolysis in rat and mouse plasma, which complicated the optimization of the conjugate. The new design will avoid these difficulties. To optimize the therapeutic protocol a dose escalation study, a time sequence study, and a multiple dose study will be performed. Numerous analyses will be performed to determine the effect of the conjugates on various bone indices, namely bone mineral density, bone mineral content, bone biomechanical, biomorphometric, and histomorphometric properties. The concept of (main chain) biodegradable HPMA copolymer drug carriers targeted to bone resorption sites is a new paradigm for the design of efficient drugs for the treatment of musculoskeletal diseases. PUBLIC HEALTH RELEVANCE The proposal addresses one of the important problems of osteoporosis treatment delivery of (anabolic) drugs to sites of bone resorption. The advantages of the proposed drug delivery systems are: selective adsorption to the tissues in bone with higher rates of bone turnover, localization of the anabolic agent (prostaglandin E1) in skeletal sites where bone formation would be beneficial, the reduction of side-effects resulting from systemic administration of free drugs, and applicability of design principles to the delivery of other drugs.

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，估计有4400万50岁及以上的男性和女性患有骨质疏松症，占美国该年龄组人口的55%。除了巨大的医疗费用外，这种情况还导致死亡率大幅增加。提出了一种治疗骨质疏松症和其他肌肉骨骼疾病的新方法：骨靶向药物传递系统；水溶性聚合物缀合物作为合成代谢剂前列腺素E1的载体。先前的实验表明，d - asp8靶向偶联物优先结合到骨吸收表面。这提供了一个独特的机会，将药物靶向活跃骨吸收的部位。另一个令人鼓舞的结果是，观察到骨形成的增加可以在单次注射结合物后持续至少一个月。提出的研究的主要目的是设计新的，有效的结合物治疗骨质疏松症。我们设计了新的，可生物降解的N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物缀合物。一个重要的设计特征是在聚合物主链（主链）中插入可降解键。因此，可以使用比不可降解载体更高的分子量，导致循环时间长，并且由于血管渗漏和每个链的靶向部分数量增加而增加骨中的积累。新设计的主要特点如下：a)新型可生物降解的HPMA基聚合物载体将由含有PGE1和靶向基团的短链HPMA共聚物片段组成，采用叠氮官能化RAFT链转移剂进行RAFT（可逆加成-破碎链转移）聚合制备。这些片段将通过与酶降解（乙炔功能化）寡肽的高效点击化学反应扩展成高分子量（长循环）载体；b)靶向D-Asp8基团将通过组织蛋白酶K敏感间隔剂与聚合物主链结合；c) PGE1通过醚键与聚合物主链结合；它将通过1,6消除基团和组织蛋白酶K敏感间隔剂连接到载体上。先前使用的酯键在人体内是稳定的，但在大鼠和小鼠血浆中容易水解，这使得缀合物的优化变得复杂。新的设计将避免这些困难。为了优化治疗方案，将进行剂量递增研究、时间序列研究和多剂量研究。将进行大量分析以确定缀合物对各种骨指标的影响，即骨矿物质密度、骨矿物质含量、骨生物力学、生物形态学和组织形态学特性。针对骨吸收部位的（主链）可生物降解的HPMA共聚物药物载体的概念是设计治疗肌肉骨骼疾病的有效药物的新范例。该提案解决了骨质疏松症治疗的一个重要问题，即向骨吸收部位递送（合成代谢）药物。所提出的药物输送系统的优点是：选择性吸附到骨骼组织中，具有较高的骨更新率，合成代谢剂（前列腺素E1）在骨骼部位的定位，骨骼形成将是有益的，减少由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。