Micellar Nanocarriers with Controlled Multivalent Ligand Presentation

具有受控多价配体呈现的胶束纳米载体

• 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
• 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

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（EPR）作用外，纳米载体还可以通过表面接枝靶配体以赋予对肿瘤细胞上细胞上调受体或组分的亲和力来主动靶向，以提高治疗功效并使副作用最小化。然而，靶向部分的存在对纳米载体的药代动力学、生物分布和肿瘤蓄积的影响仍有待量化，并且在某些情况下可能存在争议。除了诸如肿瘤生理学的生物学因素之外，靶向部分对体内肿瘤的影响也是重要的。 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。与病毒中观察到的良好调节的结构控制相反，现有纳米载体中对配体的空间分布和配体相对于颗粒表面的取向的结构控制有限，这决定了配体结合位点的可用性。 我们设计并合成了所谓的“3-螺旋胶束”，其基于两亲性3-螺旋肽-聚乙二醇（PEG）缀合物，尺寸均匀，从10-20 nm。放射性标记的3-螺旋胶束的体内稳定性已使用正电子发射断层扫描（PET）证实，聚乙二醇化15 nm胶束的α循环半衰期约为28 h。3-螺旋胶束已经克服了制备有效纳米载体所遇到的一些困难，如尺寸、货物泄漏、体内稳定性和清除率。在将目标配体连接到胶束表面后，我们应该能够实现对配体呈递的寡聚状态的控制。 我们建议（1）合成配体修饰的纳米载体，尺寸为10-20 nm，控制配体间距离和配体呈递的局部多价性;（2）进行体外研究以评估载体内化作为配体密度和多价性的函数;和（3）进行体内研究 使用两种癌症模型，即乳腺癌和前列腺癌，来评估配体密度、配体间距离和配体聚集对这些新的3-螺旋胶束的药代动力学和生物分布的影响。我们还将对有前途的胶束纳米颗粒进行免疫原性测试，以确保其作为纳米载体的临床可行性。卷曲螺旋是控制配体呈递的最常见的蛋白质基序。靶向胶束是回答主动靶向纳米载体设计原理中几个关键问题的理想模型体系。实际上，我们的研究是基于胶束纳米粒子，已经证明了许多理想的属性作为纳米载体。拟议的研究可能会导致有效的治疗方法，结合了通过EPR效应的被动靶向和乳腺肿瘤的主动靶向的优势。