Controlled delivery of polypeptide hormone calcitonin

多肽激素降钙素的控制递送

• 批准号: 8382758
• 负责人: Jagdish Singh
• 金额: $ 7.23万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8382758
• 关键词: Affect; Age-Years; American; Amino Acids; Animal Model; Attention; Biocompatible; Biological; Biological Assay; Blood; Bone Density; Bone Diseases; Bone Resorption; Calcitonin; Calcium; Cessation of life; Characteristics; Circular Dichroism; Clinical; Complex; Deterioration; Development; Disease; Equilibrium; Ethylene Glycols; Forearm Fracture; Foundations; Fracture; Gel; Gel Chromatography; Glucocorticoids; Glycolic-Lactic Acid Polyester; Goals; Half-Life; High Pressure Liquid Chromatography; Hip Fractures; Hip region structure; Hormones; Hospitalization; Hypocalcemia result; In Situ; In Vitro; Incidence; Injectable; Injection of therapeutic agent; International; Length; Light; MALDI-TOF Mass Spectrometry; Micelles; Microscopic; Modeling; Molecular Weight; Morbidity - disease rate; Mus; Osteoporosis; Paget' s Disease; Patients; Polyacrylamide Gel Electrophoresis; Polymers; Polypeptide Hormones; Postmenopause; Predisposition; Principal Investigator; Public Health; Quality of life; Rattus; Regulation; Research; Salmon; Site; Societies; Sodium Dodecyl Sulfate; Solutions; Spectroscopy, Fourier Transform Infrared; Spinal Fractures; Subcutaneous Injections; System; Techniques; Temperature; Testing; Time; Tissues; Transition Temperature; Treatment Efficacy; Vertebral column; Weight; Woman; Wrist; absorption; aqueous; base; biodegradable polymer; biomaterial compatibility; bone; bone mass; bone turnover; cardiovascular disorder risk; cardiovascular risk factor; copolymer; disability; economic cost; ethylene glycol; experience; improved; in vivo; lifetime risk; men; molecular mass; mortality; novel therapeutics; osteoporosis with pathological fracture; programs; statistics

DESCRIPTION (provided by applicant): Osteoporosis is a major public health threat in the U.S. today affecting at least 44 million Americans and up to 55% of people over 50 years of age. It is estimated that 30-50% of women and 15-30% of men will suffer a fracture related to osteoporosis in their lifetime, in other words, 1 in 3 women and 1 in 5 men will experience an osteoporotic fracture. By the year 2050, the worldwide incidence of hip fracture is projected to increase by ~300%. The combined lifetime risk for hip, forearm, and vertebral fractures coming to clinical attention is ~40%, which is equal to the risk for cardiovascular disease. Calcitonin isa polypeptide hormone with 32 amino acids and has a molecular mass of about 3500. This hormone is involved in the complex regulation of blood calcium level by inhibiting bone resorption. Calcitonin is used therapeutically for the treatment of osteoporosis, Paget's disease, and hypocalcaemia of different origin. Currently, multiple injections of calcitonin is a common practice in treating the above conditions due to its short biological half-life. It has been demonstrated that daily administration of salmon calcitonin (sCT) effectively reduces bone turnover and maintains bone mass in men and postmenopausal women. The maximum effect is reached after 2 months of continuous administration of sCT. The long-term goal of this project is to develop a polymer solution based controlled delivery system of sCT, which can deliver the hormone at a predefined rate for two months after a single subcutaneous injection. This strategy would avoid daily injections and provide optimum benefits to the osteoporotic patients. We propose to study two specific aims: (1). To synthesize and characterize temperature sensitive poly (ethylene glycol) - poly (lactide-co-glycolide) - poly (ethylene glycol) (PEG-PLGA-PEG) triblock copolymers with increasing PLGA chain length. In situ gel forming copolymer solution based controlled delivery systems of the sCT will be prepared and studied for rheological characteristics and in vitro release profiles of sCT. The stability of the released sCT as well as sCT in the gel will be evaluated using Fourier transform infrared spectroscopy, circular dichroism, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, native sodium dodecyl sulfate-polyacrylamide gel electrophoresis, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and high performance liquid chromatography techniques. Further, in vitro biocompatibility of the delivery systems will be evaluated by MTT assay. (2). To study in vivo absorption, bioassay, and therapeutic efficacy of sCT delivery systems in the glucocorticoid induced osteoporosis rat model. In vivo biocompatibility of the delivery systems will be studied in rats by light microscopic studies of the excised tissue from the injection site. The proposed efforts will significantly contribute to the development of temperature sensitive polymer based delivery systems in the form of injectable solution to deliver sCT at a controlled rate for a longe duration (~ 2 months) after a single subcutaneous injection. Development of such a novel therapeutic system is critical for successful treatment of bone diseases, especially osteoporosis in men and postmenopausal women, in order to improve patient quality of life. PUBLIC HEALTH RELEVANCE: Osteoporotic fractures are a serious cause of disability in men and postmenopausal women. Osteoporosis causes a great burden to society in terms of mortality, morbidity, and economic costs. According to the statistics from International Osteoporosis Foundation, osteoporosis causes millions of fractures annually. Osteoporosis is a major public health threat in the U.S. today affecting at least 44 million Americans and up to 55% of people over 50 years of age. Currently, multiple injections of salmon calcitonin is a common practice in treating bone diseases. The research proposed in this application would investigate the synthesis of thermosensitive triblock copolymers and their characterization. The copolymers will be used to develop controlled delivery systems in the form of injectable solutions to deliver calcitonin at a controlled rate for a longer duration (~ 2 months) after a sinle subcutaneous injection. The study would be conducted in vitro and in vivo in animal model. PHS 398/2590 (Rev. 05/01) Page Continuation Format Page

描述（由申请人提供）：骨质疏松症是美国今天至少有4400万美国人和多达50岁以上的人的主要公共卫生威胁。据估计，有30-50％的女性和15-30％的男性一生中会遭受与骨质疏松症有关的骨折，换句话说，三分之一的女性中有1名女性和五分之一的男性会经历骨质疏松性骨折。到2050年，髋部骨折的全球发病率预计将增加约300％。髋关节，前臂和椎骨骨折的终身风险综合为临床注意力约40％，这等于患心血管疾病的风险。降钙素ISA多肽激素具有32个氨基酸，分子质量约为3500。该激素通过抑制骨吸收来参与血液钙水平的复杂调节。降钙素用于治疗骨质疏松症，paget病和不同来源的低钙血症。目前，由于生物半衰期短，多次注射降钙素是治疗上述疾病的常见做法。已经证明，每天的鲑鱼降钙素（SCT）的给药可有效地减少骨骼更新，并保持男性和绝经后妇女的骨骼量。连续给予SCT 2个月后，达到最大效果。该项目的长期目标是开发基于聚合物溶液的SCT的受控递送系统，该系统可以在单一皮下注射后两个月以预定义的速率传递激素。该策略将避免每天注射，并为骨质疏松患者提供最佳益处。我们建议研究两个具体目标：（1）。合成并表征温度敏感的聚（乙二醇） - 聚（乳酸 - 糖甘露醇） - 聚（乙二醇）（PEG-PLGA-PEG）三嵌段的三嵌段共聚物随PLGA链长的增加。原位凝胶形成共聚物溶液的基于SCT的受控递送系统，并研究了SCT的流变特征和体外释放曲线。将使用傅里叶变换红外光谱，圆形二色性，十二烷基硫酸钠 - 聚丙烯酰胺凝胶电泳，十二烷基硫酸钠 - 硫酸硫酸钠 - 硫酸硫酸钠 - 硫酸盐 - 硫酸盐 - 溶质素凝胶电泳，含量的质量/iionorpeptimation，使用傅立叶变换红外光谱，圆形二色性二色酸酯凝胶电泳，对凝胶的稳定性以及凝胶中SCT的稳定性以及SCT的稳定性。 - 飞行质谱和高性能液相色谱技术。此外，将通过MTT分析评估输送系统的体外生物相容性。 （2）。研究体内吸收，生物测定和SCT递送系统在糖皮质激素诱导的骨质疏松大鼠模型中的治疗功效。输送系统的体内生物相容性将在 大鼠通过从注射部位切除的组织的光学显微镜研究。拟议的努力将以可注射溶液的形式为基于温度敏感的聚合物递送系统的开发，以在单次皮下注射后以寿命持续时间（〜2个月）以受控速率传递SCT。为了改善患者的生活质量，发展这种新型治疗系统对于成功治疗骨骼疾病，尤其是男性和绝经后妇女的骨质疏松症至关重要。 公共卫生相关性：骨质疏松性骨折是男性和绝经后妇女残疾的严重原因。骨质疏松症在死亡率，发病率和经济成本方面给社会带来了很大的负担。根据国际骨质疏松基金会的统计数据，骨质疏松症每年会导致数百万骨折。骨质疏松症是今天在美国的主要公共卫生威胁，影响至少4400万美国人，最多55％以上的人中有55％。当前，多次注射鲑鱼降钙素是治疗骨骼疾病的常见做法。该应用中提出的研究将研究热敏化三嵌段共聚物的合成及其表征。共聚物将用于以可注射溶液的形式开发受控的递送系统，以在Sinle皮下注射后更长的持续时间（〜2个月）以受控速率递送降钙素。该研究将在动物模型中在体外和体内进行。 PHS 398/2590（修订版05/01）页面延续格式页面