Multifunctional low-density lipoprotein nanoplatforms

多功能低密度脂蛋白纳米平台

• 批准号: 7239913
• 负责人: GANG ZHENG
• 金额: $ 14.39万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-12 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7239913
• 关键词: athymic mouse; biodegradable product; bioimaging /biomedical imaging; biomaterial compatibility; cell line; confocal scanning microscopy; contrast media; drug vehicle; fluorescent dye /probe; folate; low density lipoprotein; magnetic resonance imaging; nanotechnology; neoplasm /cancer photoradiation therapy; neoplastic cell; receptor binding; squamous cell carcinoma; technology /technique development

DESCRIPTION (provided by applicant): Lipoproteins are naturally-existing nanostructures (8 - 1000 nm) responsible for the transport of cholesterol and other lipids in the blood circulation. Being endogenous carriers, lipoproteins are not immunogenic and escape recognition by the reticuloendothelial system. This project will initiate a broad exploration of lipoprotein particles as diverse and biocompatible nanoplatforms, focusing on low-density lipoprotein (LDL) (22nm) as a prototype. In our multifunctional LDL-based nanoplatform (LBNP) design, the diverse targeting is achieved by conjugating certain tumor-homing molecules to the receptor-binding Lys residues exposed on the apoB-100 surface of LDL. This turns off the LDL receptor (LDLR) binding and redirects the resulting LBNP to cancer cells or tumor vasculature via other cancer signatures. The LBNP multifunctionality is achieved by incorporating near-infrared fluorescent (NIRF)/photodynamic therapy (PDT) agents and magnetic resonance imaging (MRI) probes, respectively, into the LBNP lipid core and on its phospholipids monolayer. Thus, accumulation of the MRI/NIRF probes in target cells provides a facile mechanism for amplification of the MRI/NIRF detectable signal and affords opportunities to combine the strength of both MRI (high resolution/anatomic) and NIRF (high sensitivity), whereas the selective delivery of PDT agents to tumors via these pathways also provides a facile transition between cancer detection and treatment. During the R21 phase of the grant proposal (year 01), proof-of-feasibility of the LBNP concept will be provided by conjugating folic acid to LDL to achieve high affinity toward the folate receptor. In the R33 phase (year 02 to 04), the goal is to demonstrate the binding specificity of LBNP to folate receptors and to bring new functions to the LBNP particles thereby generating two novel folate receptor-targeted nanodevices: NIR dyereconstituted LBNP for NIRF/PDT and Gd-DTPA labeled LBNP for MRI. The key questions that will be tested are: 1) Will the stability of LDL particles be compromised by the proposed LDL modifications? 2) Can folic acid-conjugated LBNP bind to folate receptor specifically without binding to LDLR and/or LDL-scavenger receptor? 3) Can folate receptor binding affinity of LBNP be maximized using the multivalency effect? 4) Can the LBNP payload be high enough to exceed the intracellular MRI detection limit? This approach is expected to generate non-immunogenic multifunctional lipoprotein nanoplatforms, thus providing a solution to common problems associated with most synthetic nanodevices, namely biocompatibility and toxicity issues.

描述（由申请人提供）： 脂蛋白是自然存在的纳米结构（8-1000 nm），负责血液循环中胆固醇和其他脂质的运输。作为内源性载体，脂蛋白不是免疫原性的，并且是网状内皮系统的逃生识别。该项目将作为多种多样的生物相容性纳米植物对脂蛋白颗粒进行广泛的探索，重点是低密度脂蛋白（LDL）（22nm）作为原型。在我们的基于LDL的多功能纳米板（LBNP）设计中，通过将某些肿瘤共归因于LDL APOB-100表面上的受体结合碱性残基结合到受体结合的裂隙残基来实现。这关闭了LDL受体（LDLR）结合，并通过其他癌症特征将所得LBNP重定向到癌细胞或肿瘤脉管系统。 LBNP多功能性是通过将近红外荧光（NIRF）/光动力疗法（PDT）药物和磁共振成像（MRI）探针（MRI）探针（MRI）探针纳入LBNP脂质核心以及其磷脂单层的单层。因此，靶细胞中MRI/NIRF探针的积累提供了一种可容纳MRI/NIRF可检测信号的功能机制，并提供了结合MRI（高分辨率/解剖学）和NIRF（高敏感性）的强度的机会，同时通过这些路径将PDT药物送给themore thecection cancer and Cancer in Cancer and Cancer and thecection cancer and thecection cance and thecection。在赠款提案的R21阶段（01年）中，通过将叶酸与LDL结合以实现对叶酸受体的高亲和力，将提供LBNP概念的可行性证明。在R33阶段（02年至04年）中，目标是证明LBNP对叶酸受体的结合特异性，并将新功能带到LBNP颗粒，从而为NIRF/PDT和GD-DPA Lab dppa for Mrri nirf/pdt lbnp lbnp lbnp lbnp lbnp lbnp lbnp labnp labnp生成两个新型的叶酸受体受体纳入的纳米dp。将要测试的关键问题是：1）提议的LDL修改会损害LDL颗粒的稳定性吗？ 2）叶酸偶联的LBNP可以与叶酸受体结合，而无需与LDLR和/或LDL-Scavenger受体结合？ 3）LBNP的叶酸受体结合亲和力可以使用多价效应最大化吗？ 4）LBNP有效载荷是否足够高以超过细胞内MRI检测极限？预计这种方法将产生非免疫原性的多功能脂蛋白纳米植物，从而为与大多数合成纳米版本相关的常见问题提供了解决方案，即生物相容性和毒性问题。