Multivalent Nano-conjugates for Targeted Penetration of and Delivery to Dense Extracellular Matrices

用于靶向渗透和递送至致密细胞外基质的多价纳米缀合物

基本信息

批准号：
10179375
负责人：
Paula T Hammond
金额：
$ 52万
依托单位：
MASSACHUSETTS INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10179375
关键词：
ADAMTS Address Anatomy Anti-Inflammatory Agents Binding Biodistribution Biological Blood Vessels Cartilage Cathepsins Cell Culture Techniques Characteristics Charge Chemistry Conjugated Carrier Cornea Degenerative polyarthritis Deposition Dexamethasone Diagnostic Disease Drug Combinations Drug Delivery Systems Drug Kinetics Drug Targeting Electrostatics Enzyme-Linked Immunosorbent Assay Enzymes Exhibits Extracellular Matrix Extravasation Family Fluorescence Resonance Energy Transfer Formulation Generations Growth Factor Heart Hemolysis Histology Hydrolysis Image Immunohistochemistry In Vitro Inflammatory Inflammatory Response Insulin-Like Growth Factor I Joints Kinetics Knowledge Label Libraries Ligaments Liver Lung Maintenance Matrix Metalloproteinases Measures Medical Meniscus structure of joint Modeling Molecular Analysis Nanoconjugate Operative Surgical Procedures Organ Oryctolagus cuniculus Penetration Peptide Hydrolases Peptides Pharmaceutical Preparations Positron-Emission Tomography Process Property Radiolabeled Rapid screening Rattus Serum Solid Neoplasm Surface System TLR4 gene Tendon structure Testing Therapeutic Therapeutic Effect Time Tissue Model Tissues Toxic effect Toxicology Translations Trauma Vascular System Work animal imaging animal tissue base cartilage regeneration cartilage repair chemical function clinical biomarkers crosslink cytokine density design effective therapy efficacy evaluation experimental study imaging agent imaging facilities in vivo inflammatory marker inhibitor/antagonist interest joint inflammation nanocarrier nanomaterials nanomedicine nanoparticle particle repaired residence small molecule therapeutic evaluation trafficking transcriptome sequencing uptake

项目摘要

Although nanoparticles have been found to be effective in delivery to more traditional vascularized organs and tissues, there are different challenges for nanoparticle transport in tissues that lack a vascular system to assist in penetration into the tissue. Here we propose a systematic approach to the design of nanomaterials systems that are capable of deep penetration and delivery of agents into avascular tissues. The proposed work will focus on establishing sets of materials design concepts to enhance transport into and through these tissues based on size, charge density and presentation, targeting and dynamic materials chemistries. In the Aim 1, we will develop two promising families of multivalent drug nanocarriers with modular design, each presenting unique advantages for tissue penetration. The transport of these nanocarriers will then be examined as a function of size and charge using ex vivo tissue models to rapidly screen libraries of nanocarriers and identify optimal size/charge characteristics for tissues of interest. We will examine transport in three unique avascular tissue types: cartilage, meniscus and cornea to understand similarities or differences in design requirements and optimal transport characteristics for a range of avascular tissue types. Further translation of this Aim is anticipated to provide fundamental knowledge regarding how to address other similar barrier tissues in the context of drug delivery. Treatment of cartilage to address conditions such as osteoarthritis presents a particularly important medical challenge, and is the disease focus for the later Aims of these studies; however, successful demonstration of this system in the first Aim will be applicable to other tissues and conditions, including delivery to the cornea and joint meniscus. To enable a more tissue-responsive delivery approach, both pH responsive and enzyme degradable linkers will be examined in Aim 2 for the conjugation of therapeutics, with the focus on conjugation of IGF-1, a growth factor that can facilitate cartilage regeneration in early stage osteoarthritis. Optimized versions of the nanocarriers will be studied in an established in vivo using an early surgical trauma rat model to evaluate the efficacy of IGF-1 treatments with the nondegradable, hydrolytic, and protease-activated degradable linkers and determine in vivo real-time pharmacokinetics versus free IGF-1. Cartilage treatment studies will be carried out in this model for IGF-1 delivery. Finally, an additional aspect of this study will be the design of nanoconjugates that release drug selectively to regions of tissue matched to the different nanocarrier transport properties determined in earlier Aims, including degree of penetration and residence time within the tissue. Combination treatments for small molecule drugs including dexamethasone and TLR4 inhibitors will be conjugated to carriers optimal for each drug, in combination with the top IGF-1 formulation. We will evaluate the therapeutic effects of the combinations in a cytokine-challenged ex vivo cartilage tissue model by measuring inflammatory markers, matrix deposition and maintenance, and kinetics of cartilage repair. 1

尽管已经发现纳米颗粒有效地传递到传统的血管化器官和组织，对于缺乏血管系统的组织中的纳米颗粒传输面临不同的挑战在渗透到组织中。在这里，我们提出了一种系统的纳米材料系统设计方法能够深入渗透和将剂传递到血管组织中。拟议的工作将集中建立一组材料设计概念集，以增强基于这些组织的运输大小，电荷密度和表现，靶向和动态材料化学。在目标1中，我们将发展具有模块化设计的两个有前途的多价药物纳米载体家族，每个载体都具有独特的优势用于组织穿透。然后，将检查这些纳米载体的运输作为大小和电荷的函数使用离体组织模型快速筛选纳米载体的库，并确定最佳尺寸/电荷感兴趣的组织的特征。我们将检查三种独特的血管组织类型的运输：软骨，半月板和角膜以了解设计要求和最佳运输方面的相似性或差异各种血管组织类型的特征。预计该目标的进一步翻译将提供关于如何在药物输送的背景下如何解决其他类似屏障组织的基本知识。软骨治疗以解决诸如骨关节炎等疾病的治疗挑战，这是这些研究后来目标的重点。但是，成功的演示第一个目标中的该系统将适用于其他组织和条件，包括交付到角膜和联合半月板。为了实现更多的组织响应递送方法，pH响应式和酶将在AIM 2中检查可降解的链接器以进行治疗，重点是共轭 IGF-1的生长因子可以促进早期骨关节炎的软骨再生。优化版本将使用早期手术创伤大鼠模型在体内研究纳米载体的含量 IGF-1处理的功效，可通过可降解，水解和蛋白酶降解的连接器并确定体内实时药代动力学与自由IGF-1。软骨治疗研究将进行在此模型中进行IGF-1传递。最后，这项研究的另一个方面将是纳米缀合物的设计该药物有选择地释放到与不同纳米载体传输特性匹配的组织区域在较早的目标中确定，包括在组织内的穿透程度和停留时间。组合小分子药物在内的治疗包括地塞米松和TLR4抑制剂将与载体偶联每种药物最佳，结合顶部IGF-1配方。我们将评估通过测量炎症标记，在细胞因子挑战的离体软骨组织模型中的组合，基质沉积和维护，以及软骨修复的动力学。 1