Controlled delivery of polypeptide hormone calcitonin

多肽激素降钙素的控制递送

• 批准号: 8515282
• 负责人: Jagdish Singh
• 金额: $ 6.85万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515282
• 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.

描述（由申请人提供）：骨质疏松症是当今美国主要的公共卫生威胁，影响至少4400万美国人和高达55%的50岁以上人群。据估计，30-50%的女性和15-30%的男性在其一生中将遭受与骨质疏松症有关的骨折，换句话说，三分之一的女性和五分之一的男性将经历骨质疏松性骨折。到2050年，预计全世界髋部骨折的发病率将增加约300%。引起临床关注的髋部、前臂和椎骨骨折的综合终生风险约为40%，与心血管疾病的风险相当。降钙素伊萨一种由32个氨基酸组成的多肽激素，分子量约为3500。这种激素通过抑制骨吸收参与血钙水平的复杂调节。降钙素在治疗上用于治疗骨质疏松症、佩吉特病和不同来源的低钙血症。目前，由于降钙素的生物半衰期短，多次注射降钙素是治疗上述病症的常见做法。已经证明，每日施用鲑鱼降钙素（sCT）有效地降低男性和绝经后女性的骨转换并维持骨量。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一种基于聚合物溶液的sCT控释系统，该系统可以在单次皮下注射后以预定速率递送激素两个月。这种策略将避免每天注射，并为阿尔茨海默病患者提供最佳益处。我们建议研究两个具体目标：（1）。合成了聚乙二醇-聚丙交酯-乙交酯-聚乙二醇（PEG-PLGA-PEG）三嵌段共聚物，并对其进行了表征。将制备基于sCT的原位凝胶形成共聚物溶液的控释系统，并研究sCT的流变学特性和体外释放曲线。将使用傅里叶变换红外光谱、圆二色谱、十二烷基硫酸钠-聚丙烯酰胺凝胶电泳、天然十二烷基硫酸钠-聚丙烯酰胺凝胶电泳、基质辅助激光解吸/电离飞行时间质谱和高效液相色谱技术评价释放的sCT以及凝胶中sCT的稳定性。此外，将通过MTT试验评价输送系统的体外生物相容性。（二）、研究sCT给药系统在糖皮质激素诱导的骨质疏松大鼠模型中的体内吸收、生物测定和治疗效果。将研究输送系统的体内生物相容性， 通过从注射部位切除组织的光学显微镜研究大鼠。所提出的努力将显著有助于开发注射溶液形式的基于温度敏感聚合物的递送系统，以在单次皮下注射后以受控速率递送sCT持续较长时间（约2个月）。开发这种新型治疗系统对于成功治疗骨疾病，特别是男性和绝经后女性的骨质疏松症，以改善患者的生活质量至关重要。