Thermally-Induced Intra-Articular Drug Delivery System

描述（由申请人提供）：抗炎药、IL-1受体拮抗剂（IL 1 Ra）和TNF-α阻断抗体已显示可显著改变炎性关节疾病的进展。虽然这些药物具有影响骨关节炎治疗的显著潜力，但与所需的全身给药方案相关的严重副作用限制了它们在骨关节炎中的单一关节病理学的应用。需要一种有效的机制来将这些药物直接递送到关节空间，同时提供药物有效性所建议的高浓度和频繁给药。本研究的目的是开发一种新型的关节内给药系统，将有效地将这些疾病改善药物直接输送到关节间隙。弹性蛋白样多肽（ELP）将作为新开发的药物递送系统的基础，由此ELP在注射到关节间隙中时在体温下被热触发以形成大的微米尺寸聚集体。我们建议，这些聚集体可以捕获蛋白质药物，从而作为一个“仓库”的药物释放随时间的推移。我们进一步提出了ELP可以作为这些蛋白质药物的药物载体的两种具体机制：（1）通过混合和热引发聚集体形成（> 35 ℃）后蛋白质药物的物理包埋，或（2）通过设计ELP-药物融合蛋白，当热引发时将经历聚集体形成。在这个项目中，我们建议研究这两个概念应用于释放一种蛋白质药物，IL 1 Ra，作为第一个概念验证。我们建议开展以下工作：（1）合成将IL 1 Ra物理捕获到聚集体中的ELP，并评估IL 1 Ra在大鼠模型中的生物分布动力学;和（2）合成ELP和IL 1 Ra的融合蛋白，并类似地评估IL 1 Ra在大鼠中的生物分布。从ELP释放的蛋白质药物，无论是作为可溶性药物还是融合蛋白，也将在体外进行评价，以确定释放动力学、与靶（IL-1受体1）的结合活性和调节T淋巴细胞增殖的生物活性。我们的中心假设是，关节内注射用于IL 1 Ra的基于ELP的“药物贮库”将增加这种重要的疾病修饰药物在关节间隙中的半衰期，从而提供作为骨关节炎的高效治疗的潜力。

DESCRIPTION (provided by applicant): The anti-inflammatory drugs, IL-1 receptor antagonist (IL1Ra) and TNF-alpha blocking antibodies, have been shown to dramatically modify the progression of inflammatory joint disease. While these drugs have significant potential to impact treatment of osteoarthritis, serious side effects associated with the required systemic administration protocol limits their application to single joint pathology in osteoarthritis. There is a need for an effective mechanism to deliver these drugs directly to the joint space, while providing for the high concentrations and frequent dosing suggested for drug effectiveness. The objective of this study is to develop a novel intra-articular drug delivery system that will be effective for delivering these disease-modifying drugs directly to the joint space. Elastin-like polypeptides (ELPs) will serve as the basis for the newly developed drug delivery system, whereby ELPs are thermally triggered to form large, micron size aggregates at body temperature upon injection into the joint space. We propose that these aggregates can entrap protein drugs and thus serve as a "depot" for drug release over time. We further propose two specific mechanisms by which ELPs can serve as drug carriers for these protein drugs: (1) by physical entrapment of the protein drug following mixing and thermally-initiated aggregate formation (> 35 degrees C), or (2) by design of an ELP-drug fusion protein that will undergo aggregate formation when thermally-initiated. In this project, we propose work to study these two concepts applied to the release of one protein drug, IL1Ra, as a first proof-of-concept. We propose work to: (1) synthesize ELPs that physically entrap IL1Ra into aggregates and evaluate the kinetics of IL1Ra biodistribution in a rat model; and (2) synthesize fusion proteins of ELPs and IL1Ra and similarly evaluate IL1Ra biodistribution in the rat. The protein drugs released from the ELPs, either as soluble drug or fusion protein, will also be evaluated in vitro to determine kinetics of release, binding activity to target (IL-1 receptor 1) and biological activity in regulating T-lymphocyte proliferation. It is our central hypothesis that intra-articular injection of an ELP-based "drug depot" for IL1Ra will increase the half-life of this important disease-modifying drug in the joint space, and thus provide the potential to serve as a highly effective treatment for osteoarthritis.