BONE TARGETED DELIVERY OF ANABOLIC AGENTS

合成代谢药物的骨靶向输送

基本信息

批准号：
8120446
负责人：
JINDRICH H. KOPECEK
金额：
$ 29.5万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8120446
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 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 Gene Expression Genes Goals Health Hormone replacement therapy Hormones 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 Osteopenia Osteoporosis Parathyroid gland 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 WFDC2 protein improved in vivo indexing macromolecule men methacrylamide mortality new technology novel novel strategies osteogenic phenylalanylleucine polymerization prolyl-glycyl-glycine protein aminoacid sequence pyridine receptor research study skeletal skeletal disorder skeletal tissue targeted delivery tartrate-resistant acid phosphatase therapeutic evaluation trafficking trithiocarbonate

项目摘要

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卫生威胁。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，占美国该年龄段人口的 55%。除了巨大的医疗费用之外，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，即采用骨靶向的靶向药物输送系统；水溶性聚合物缀合物作为合成代谢剂前列腺素 E1 的载体。先前的实验已证明 D-Asp8 靶向缀合物优先掺入骨吸收表面。这提供了将药物靶向活跃骨吸收部位的独特机会。另一个令人鼓舞的结果是观察到单次注射结合物后骨形成的增加可以持续至少一个月。本研究的主要目的是设计新颖、有效的结合物来治疗骨质疏松症。我们设计了新型可生物降解的 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将可降解键插入聚合物主链（主链）中。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，并且由于脉管系统渗漏和每条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 HPMA 基聚合物载体将由短遥爪 HPMA 共聚物片段组成，含有 PGE1 和靶向部分，通过 RAFT（可逆加成断裂链转移）聚合制备，使用叠氮基官能化的 RAFT 链转移剂。这些片段将通过与可酶降解（乙炔官能化）寡肽的高效点击化学反应延伸成高分子量（长循环）载体； b) 靶向 D-Asp8 基团将通过组织蛋白酶 K 敏感间隔基与聚合物主链结合； c) PGE1将通过醚键结合到聚合物主链上；它将通过 1,6-消除基团和组织蛋白酶 K 敏感间隔区连接到载体。以前使用的酯键在人体中稳定，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数的影响，即骨矿物质密度、骨矿物质含量、骨生物力学、生物形态计量学和组织形态计量学特性。针对骨吸收位点的（主链）可生物降解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。公共卫生相关性该提案解决了向骨吸收部位输送（合成代谢）药物治疗骨质疏松症的重要问题之一。所提出的药物输送系统的优点是：选择性吸附到骨骼中的组织，具有较高的骨转换率，将合成代谢剂（前列腺素E1）定位在有利于骨形成的骨骼部位，减少由此产生的副作用从游离药物的系统给药，以及设计原理对其他药物输送的适用性。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hybrid hydrogels self-assembled from graft copolymers containing complementary β-sheets as hydroxyapatite nucleation scaffolds.

DOI：
10.1016/j.biomaterials.2011.04.014
发表时间：
2011-08
期刊：
BIOMATERIALS
影响因子：
14
作者：
Wu, Larisa C.;Yang, Jiyuan;Kopecek, Jindrich
通讯作者：
Kopecek, Jindrich

Efficiency of high molecular weight backbone degradable HPMA copolymer-prostaglandin E1 conjugate in promotion of bone formation in ovariectomized rats.

DOI：
10.1016/j.biomaterials.2013.05.003
发表时间：
2013-09
期刊：
BIOMATERIALS
影响因子：
14
作者：
Pan, Huaizhong;Sima, Monika;Miller, Scott C.;Kopeckova, Pavla;Yang, Jiyuan;Kopecek, Jindrich
通讯作者：
Kopecek, Jindrich

Release of prostaglandin E(1) from N-(2-hydroxypropyl)methacrylamide copolymer conjugates by bone cells.