Micellar Nanocarriers with Controlled Multivalent Ligand Presentation

具有受控多价配体呈现的胶束纳米载体

基本信息

批准号：
8583975
负责人：
Ting Xu
金额：
$ 18.46万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-05 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8583975
关键词：
Address Adverse effects Affinity Amino Acid Motifs Antibodies Avidity Binding Binding Sites Biodistribution Biological Biological Factors Biological Models Blood Circulation Breast Cancer Model Caliber Cancer Model Cell surface Cells Characteristics Chemistry Clinical Devices Diagnosis Digestion Disease Doxorubicin Drug Carriers Drug Formulations Drug Kinetics Employee Strikes Encapsulated Ensure Equilibrium Extravasation Family Future Goals Half-Life Homing Image In Vitro Knowledge Lateral Lead Ligand Binding Ligands Liver Malignant neoplasm of prostate Mammary Neoplasms Micelles Modeling Molecular Target Nature Outcome Pathway interactions Penetration Peptides Performance Pharmaceutical Preparations Physiology Polyethylene Glycols Positron-Emission Tomography Property Radiolabeled Relative (related person)Reticuloendothelial System Serum Proteins Site Solubility Spatial Distribution Specificity Spleen Substrate Interaction Surface System Testing Therapeutic Therapeutic Index Time Tissues Toxic effect Translating Treatment Efficacy Tumor Tissue Virus Xenograft procedure aqueous base cancer cell cancer therapy density design immunogenicity improved in vivo malignant breast neoplasm meetings nanocarrier nanoparticle neoplastic cell particle public health relevance radiotracer receptor small molecule tumor uptake

项目摘要

DESCRIPTION (provided by applicant): In addition to the enhanced permeation and retention (EPR) effect, nanocarriers can be actively targeted to improve the efficacy of treatment and minimize side effects by surface grafting target ligands to impart an affinity for cellular upregulated receptors or components on tumor cells. However, the effects of the presence of a targeting moiety on the pharmacokinetics, biodistribution and tumor accumulation of nanocarriers still remain to be quantified and can be controversial in some cases. In addition to the biological factors such as tumor physiology, the influence of a targeting moiety on the in vivo pathway and fate of nanocarriers should depend on the nature of the targeting moiety as well as its spatial distribution on the nanocarrier surface. In contrast to well-regulated structural contrl seen in viruses, there is limited structural control in existing nanocarriers over the spatial distribution of ligands and the orientation of ligand relative to the particle surface that determies the availability of ligand binding sites. We have designed and synthesized so-called "3-helix micelles" that are uniform in size from 10-20 nm based on amphiphilic 3-helix peptide-polyethylene glycol (PEG) conjugates. The in vivo stability of the radiolabeled 3-helix micelles have been confirmed using positron emission tomography (PET) and the alpha circulatory half-life of PEGylated 15 nm micelle is ~28 h. 3-helix micelles already overcame several difficulties encountered to prepare effective nanocarriers such as size, cargo leakage, in vivo stability and clearance. Upon attaching target ligands to the surface of micelles, we should be able to achieve control over oligomeric state of ligand presentation. We propose to (1) synthesize ligand decorated nanocarriers, 10-20 nm in size with control over the inter-ligand distance and local multivalency of ligand presentation; (2) perform in vitro studies to evaluate the carrier internalization as a function of ligand density and multivalency; and (3) carry out in vivo studies use two cancer models, i.e. breast cancer and prostate cancer, to evaluate the effect of ligand density, inter-ligand distance and ligand clustering on the pharmacokinetics and biodistribution of these new 3-helix micelles. We will also perform immunogenicity tests on promising micellar nanoparticles to ensure their clinical viability as nanocarriers. Coiled-coil is the most common protein motif to control ligand presentation. The targeted micelles are ideal model system to answer several critical questions regarding the design principle of active targeting nanocarriers. Practically, our studies are based on micellar nanoparticles that have already demonstrated many desirable attributes as nanocarriers. Proposed studies may potentially lead to effective therapeutics with the combined advantages of both passive targeting via EPR effect and active targeting for breast tumors.

描述（由申请人提供）：除了增强的渗透和保留效应（EPR）效应外，还可以将纳米载体积极靶向，以提高治疗的功效，并通过表面嫁接靶配体的表面接收靶配体以赋予对细胞上置式受体或成分对肿瘤细胞的亲和力的副作用。但是，靶向部分的存在对药代动力学的影响，纳米载体的生物分布和肿瘤积累仍然有待量化，在某些情况下可能会引起争议。除了诸如肿瘤生理的生物学因素之外，靶向部分对体内的影响纳米载体的途径和命运应取决于靶向部分的性质及其在纳米载体表面上的空间分布。与病毒中观察到的结构障碍相反，现有纳米载体的结构控制有限，而配体的空间分布和配体相对于颗粒表面的方向，这决定了配体结合位点的可用性。我们已经设计和合成了所谓的“ 3螺旋胶束”，其大小均匀，基于两亲性3-螺旋肽多乙二醇（PEG）结合物。使用正电子发射断层扫描（PET）证实了放射性标记的3螺旋胶束的体内稳定性，而Pegypated 15 nm胶束的α循环半衰期为〜28 h。 3-螺旋胶束已经克服了遇到的几个困难，以准备有效的纳米载体，例如尺寸，货物泄漏，体内稳定性和清除率。将靶配体连接到胶束表面后，我们应该能够控制配体呈现的寡聚状态。我们建议（1）合成配体装饰的纳米载体，尺寸为10-20 nm，控制配体距离和配体呈现的局部多价。（2）进行体外研究，以评估载体内在化是配体密度和多价性的函数；（3）进行体内研究使用两种癌症模型，即乳腺癌和前列腺癌，以评估配体密度，配体间距离和配体聚类对这些新3螺旋胶束的药代动力学和生物分布的影响。我们还将对有希望的胶束纳米颗粒进行免疫原性测试，以确保它们作为纳米载体的临床生存能力。盘绕螺旋是控制配体呈递的最常见蛋白质基序。目标胶束是理想的模型系统，可以回答有关主动靶向纳米载体的设计原理的几个关键问题。实际上，我们的研究基于胶束纳米颗粒，这些胶束纳米颗粒已经显示出许多理想的属性作为纳米载体。拟议的研究可能有可能导致有效的治疗剂，而通过EPR效应和对乳腺肿瘤的主动靶向靶向的综合优势。