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PEG-like Multimodal Nanoprobes for Imaging Enhanced Permeability Retention

用于成像增强渗透性保留的类 PEG 多峰纳米探针

基本信息

批准号：
9263761
负责人：
Marc David Normandin
金额：
$ 38.91万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9263761
关键词：
A549 Albumins Animal Model Arthritis Behavior Binding Biological Biological Markers Bioluminescence Breast Caliber Cathepsins B Cell Culture Techniques Cells Clinic Clinical Collagen-Induced Arthritis Colon Cultured Cells Detection Dextrans Dimensions Dose-Limiting Drug Kinetics Exhibits Fluorescence Fluorescence Microscopy Fluorochrome HT29 Cells Hepatic Image Image Enhancement Immunoglobulin G Inflammation Inflammatory Injection of therapeutic agent Joints Kidney Label Lesion Ligands Liposomes Liver Luciferases Lung Malignant Neoplasms Mediating Methods Microscopy Modeling Neoplasm Metastasis Optics Organ Pathology Peptide Hydrolases Performance Permeability Pharmaceutical Preparations Polymers Positron-Emission Tomography Property Radiation Radioactivity Radiolabeled Serum Time Tissues Translations Tumor Markers Xenograft Model Xenograft procedure base biological systems clinical imaging clinical translation design glomerular filtration improved melanoma multimodality nanomaterials nanomedicine nanoprobe patient stratification pharmacokinetic model pre-clinical pre-clinical research public health relevance quantum scaffold scavenger receptor single photon emission computed tomography tumor uptake

项目摘要

DESCRIPTION (provided by applicant): PEG-like Multimodal Nanoprobes (PMN's) are passively targeted nanomaterials for determining the mechanism of retention obtained with enhanced permeability and retention (EPR), for imaging and modeling EPR pre-clinically, and for the eventual imaging of the EPR biomarker in the clinic. EPR is the slow accumulation (12-72 h post injection) of long-circulating nanomedicines (e.g. drug-polymer conjugates, liposomes) in tumors and inflammatory lesions. PMN's consist of DOTA, a PEG, and a fluorochrome attached to a (DOTA)Lys-Cys scaffold. PEG improves fluorochrome performance and endows a PMN with a PEG- determined (rather than fluorochrome-determined) behavior in biological systems. PMN's differ from other EPR nanoprobes (liposomes, albumin, dextrans) by exhibiting a surprising renal (rather than hepatic) elimination, even when the PEG determined dimensions of a PMN exceed the size limit of glomerular filtration, and even when the PMN exhibits the extremely slow whole body clearance needed for a large EPR uptake. The PMN's fluorochrome allows fluorescence-based determination of PMN in tissues (post injection microscopy) or cultured cells (FACS), and will be used to determine the mechanism of PMN retention. DOTA allows 111In3+ radiolabeling for modeling EPR by SPECT and for eventual clinical imaging by SPECT or PET. PMN-EPR imaging maybe employed for the primary detection of tumors or inflammatory lesions, or to stratify patients for the use of long circulating nanomedicines (e.g. liposomes) used in the treatment of their cancer or arthritis.

描述（由申请人提供）：PEG样多模态纳米探针（PMN）是被动靶向纳米材料，用于确定通过增强渗透性和保留（EPR）获得的保留机制，用于临床前EPR成像和建模，以及用于临床中EPR生物标志物的最终成像。EPR是长循环纳米药物（例如药物-聚合物缀合物、脂质体）在肿瘤和炎性病变中的缓慢积累（注射后12-72小时）。PMN由连接到（DOTA）Lys-Cys支架的DOTA、PEG和荧光染料组成。PEG改善荧光染料的性能，并赋予PMN在生物系统中PEG决定的（而不是荧光染料决定的）行为。PMN与其他EPR纳米探针（脂质体、白蛋白、葡聚糖）的不同之处在于表现出令人惊讶的肾（而不是肝）消除，即使当PMN的PEG确定的尺寸超过肾小球过滤的尺寸限制时，并且即使当PMN表现出大EPR摄取所需的极慢的全身清除时。PMN的荧光染料允许基于荧光测定组织（注射后显微镜检查）或培养细胞（FACS）中的PMN，并将用于确定PMN保留的机制。DOTA允许111 In 3+放射性标记用于通过SPECT建模EPR和通过SPECT或PET进行最终临床成像。PMN-EPR成像可用于肿瘤或炎性病变的初步检测，或对患者进行分层，以使用用于治疗其癌症或关节炎的长循环纳米药物（例如脂质体）。