Heat enhanced molecular delivery to growth plates for targeted bone lengthening

热增强分子递送至生长板以实现有针对性的骨延长

• 批准号: 8811682
• 负责人: Maria Anne Serrat
• 金额: $ 38.31万
• 依托单位: MARSHALL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811682
• 关键词: Adverse effects; Biological Markers; Blood Vessels; Blood Volume; Bone Diseases; Bone Growth; Bone Lengthening; Cartilage; Cartilage Matrix; Child; Childhood; Clinical; Data; Development; Disease; Disease model; Dose; Drug Delivery Systems; Drug Targeting; Endocrine System Diseases; Epiphysial cartilage; Etiology; Failure; Foundations; Genetic; Goals; Grant; Growth; Growth Disorders; Growth Hormone Receptor; Health; Heating; Housing; Image; Inequality; Injection of therapeutic agent; Injury; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Intervention; Knockout Mice; Knowledge; Label; Laboratory Animals; Lead; Length; Life; Limb structure; Link; Measures; Mediating; Methodology; Methods; Microscopy; Mission; Modality; Modeling; Molecular; Mus; Musculoskeletal Diseases; Operative Surgical Procedures; Outcome; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phosphorylation; Physicians; Physiological; Physiology; Population; Problem Solving; Procedures; Protocols documentation; Proxy; Public Health; Quality of life; Regimen; Relative (related person); Research; Scientist; Side; Signal Transduction; Site; Skeleton; Somatomedins; Systemic disease; Techniques; Temperature; Testing; Therapeutic; Time; Toxic effect; Tracer; Translational Research; Transport Process; Vascular blood supply; Walking; Weaning; base; bone; cold temperature; combat; cost; cost effective; design; effective therapy; improved; in vivo; in vivo Model; in vivo imaging; inhibitor/antagonist; innovation; juvenile animal; limb bone; molecular size; multidisciplinary; novel; receptor; skeletal; socioeconomics; solute; therapeutic target; tibia; uptake

DESCRIPTION (provided by applicant): Linear growth deficiencies have multiple etiologies, ranging from injury and illness to genetic bone disease. Bone elongation disorders are particularly challenging to treat because of the relative inability to regulate molecular delivery o the growing skeleton. The primary obstacle to successful clinical intervention is lack of molecular delivery to the growing skeleton. The primary obstacle to successful clinical intervention is lack of methods for targeting therapeutics to growth plate cartilage, which does not have a penetrating blood supply. Existing procedures for limb lengthening involve invasive surgery or drug regimens, which are to date only partially effective. Data generated by the applicant show that localized heating increases molecular uptake in growth plate cartilage in vivo, suggesting that heat could be a noninvasive and inexpensive alternative for augmenting delivery of bone-lengthening drugs. The long-term goal is to identify physiological mechanisms underlying temperature-enhanced bone elongation in the growth plate. The overall objective of the problem-solving proposal is to determine whether heat augments the bone-lengthening effects of systemic growth regulators. Insulin-like growth factor (IGF)-I is a potent stimulator of linear growth and part of a drug regimen used in children. The central hypothesis, based on strong preliminary data and tested under two specific aims using dynamic in vivo multiphoton microscopy, is that heat localizes delivery of systemic IGF-I into growth plates to promote additive bone lengthening. Specific Aim 1 uses in vivo cartilage imaging to determine dose, timing, and temperatures that maximize IGF-I uptake in 5-week-old mouse tibial growth plates. Injections of fluorescently labeled IGF-I and size proxy tracers will be given to quantify molecular uptake and clearance in the growth plate. Real time imaging will be used to determine delivery rate and total volume of labeled molecules in the growth plate and surrounding vasculature after timed injections. Permeability of the vessels and matrix will be measured at different doses and temperatures. Specific Aim 2 uses a novel limb heating model to determine if heat-enhanced IGF-I uptake in growth plates causes unilateral limb lengthening, analyzed by quantifying growth rate and biomarkers of IGF-I activation in heat-treatable tibiae. Injections of IGF-I and its receptor antagonist will explicitly show if heat-enhanced uptake increases bone length. IGF-I deficient growth hormone receptor knockout mice will be used to test the drug-targeting efficacy of heat in a disease model. The rationale is to facilitate design of heat based drug-targeting approaches to enhance length at specific skeletal sites using noninvasive techniques. This project is innovative by using multiphoton imaging to assess growth plate physiology at the cellular level in vivo, in a dynamic way not possible with other methodologies. This contribution is significant because it can yield transformative findings that mechanistically link heat, bone lengthening, and vascular access to growth plates. Such results could fundamentally shift the approach that physicians take in treating a spectrum of growth plate disorders, leading to new therapies with better outcomes by reducing amount, toxicity and costs of high-dose systemic pharmaceuticals.

描述（由申请人提供）：线性生长缺陷有多种病因，从损伤和疾病到遗传性骨病。骨延伸障碍是特别具有挑战性的治疗，因为相对无法调节分子输送到生长的骨骼。成功的临床干预的主要障碍是缺乏分子输送到生长的骨骼。临床干预成功的主要障碍是缺乏针对生长板软骨的靶向治疗方法，因为生长板软骨没有穿透性的血液供应。现有的肢体延长方法包括侵入性手术或药物治疗，迄今为止仅部分有效。申请人生成的数据表明，局部加热会增加生长板软骨体内的分子摄取，这表明加热可能是一种无创且廉价的增加骨延长药物递送的替代方法。长期目标是确定生长板中温度增强骨伸长的生理机制。解决问题的建议的总体目标是确定热量是否增加了全身生长调节剂的骨延长效果。胰岛素样生长因子(IGF)- 1是一种有效的刺激因子

项目成果

Unilateral heat accelerates bone elongation and lengthens extremities of growing mice.

• DOI: 10.1002/jor.22812
• 发表时间: 2015-05
• 期刊: Journal of orthopaedic research : official publication of the Orthopaedic Research Society
• 作者: Serrat MA;Schlierf TJ;Efaw ML;Shuler FD;Godby J;Stanko LM;Tamski HL
• 通讯作者: Tamski HL