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）：骨质疏松症是主要的公共卫生威胁。目前，骨质疏松症估计有4,400万名50岁及50岁以上的男女，占美国该年龄段人口的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。提出了一种新的治疗骨质疏松症和其他肌肉骨骼疾病的方法，该方法采用靶向骨骼的靶向药物递送系统。水溶性聚合物共轭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靶向的共轭物优先掺入骨吸收表面上。这提供了一个独特的机会，可以将药物靶向活跃的骨吸收部位。另一个令人鼓舞的结果是，观察到骨骼形成的增加至少可以在单一注射结合后一个月持续一个月。拟议的研究的主要目的是设计新颖的，有效的结合物来治疗骨质疏松症。我们设计了新的，可生物降解的N-（2-羟基丙酰基）甲基丙烯酰胺（HPMA）共聚物共轭物。一个重要的设计特征是将可降解键插入聚合物主链（骨干）中。因此，可以使用比不可分解的载体更高的分子量，从而导致长时间循环时间和由于漏水脉管系统而增加的骨骼积聚，并且每个链中靶向部分的靶向部分增加。新设计的主要特征如下：a）新型可生物降解的基于HPMA的聚合物载体将由短链球菌HPMA共聚物段组成，其中包含PGE1和靶向部分，由RAFT（可逆的加法链链转移）制备，使用AZIDO-FORCTICATION触发的Raft-intimentigation ructized Rapt Chaber thraft Chang transfers组成。这些段将通过高效的咔啉反应，并具有酶上可降解（乙炔官能化的）寡肽，将这些片段扩展到高分子量（长循环）载体。 b）靶向D-ASP8组将通过组织蛋白酶敏感的垫片与聚合物主链结合； c）PGE1将通过醚键结合到聚合物主链；它将通过1,6-脱离组和一个敏感的垫片连接到载体。先前使用的酯键在人类中是稳定的，但易受大鼠和小鼠血浆中水解的影响，这使结合物的优化变得复杂。新设计将避免这些困难。为了优化治疗方案剂量升级研究，将进行时间序列研究和多次剂量研究。将进行大量分析，以确定偶联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）可生物降解的HPMA共聚物药物载体是设计有效药物以治疗肌肉骨骼疾病的新范式。公共卫生相关性该提案解决了骨质疏松症治疗（合成代谢）药物到骨吸收部位的重要问题之一。拟议的药物输送系统的优点是：在骨骼更新率较高的骨骼中的组织，在骨骼部位的定位剂（Prostaglandin E1）的定位，骨骼形成是有益的，减少副作用，从而减少副作用，从而减少副作用，从而导致自由药物的全身性药物适用于设计原理对其他药物的适用性。

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）

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

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