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

• 批准号: 8610478
• 负责人: LEE JOSEPHSON
• 金额: $ 42.49万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-22 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8610478
• 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 Arthritis; Colon; Cultured Cells; Detection; Dextrans; Dimensions; Dose-Limiting; Drug Kinetics; Exhibits; Fluorescence; Fluorescence Microscopy; Fluorochrome; HT29 Cells; Hepatic; Image; 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; Patients; Peptide Hydrolases; Performance; Permeability; Pharmaceutical Preparations; Polymers; Positron-Emission Tomography; Property; Radiation; Radioactivity; Radiolabeled; Serum; Time; Tissues; Translations; Xenograft Model; Xenograft procedure; base; biological systems; design; dextran; glomerular filtration; improved; melanoma; nanomaterials; nanomedicine; nanoprobe; pharmacokinetic model; pre-clinical; pre-clinical research; public health relevance; quantum; radiotracer; scaffold; scavenger receptor; single photon emission computed tomography; tumor; uptake

Abstract 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.

摘要 聚乙二醇类多模式纳米探针(PMN‘s)是一种被动靶向的纳米材料，用于确定 通过增强渗透性和保留率(EPR)获得的保留率机制，用于成像和建模 EPR在临床前的应用，以及EPR生物标志物在临床上的最终成像。EPR是最慢的 长循环纳米药物的累积(注射后12-72小时)(例如药物-聚合物结合物， 脂质体)在肿瘤和炎症性病变中。PMN由DOTA、聚乙二醇乙二醇酯和荧光素组成 (DOTA)Lys-Cys脚手架。聚乙二醇乙二醇酯提高了荧光性能，并赋予PMN一种聚乙二醇胺- 生物系统中确定的(而不是荧光素决定的)行为。PMN与其他EPR不同 纳米探针(脂质体、白蛋白、葡聚糖)通过表现出令人惊讶的肾脏(而不是肝脏)消除， 即使当聚乙二醇所确定的PMN的尺寸超过肾小球滤过的尺寸限制时，甚至 当PMN表现出摄取大量EPR所需的极慢的全身清除时。PMN的 荧光显色法可测定组织中PMN(注射后显微镜)或 培养的细胞(FAC)，并将用于确定PMN的滞留机制。DOTA支持111英寸3+ 放射性标记用于通过SPECT模拟EPR以及最终通过SPECT或PET进行临床成像。PMN-EPR 成像可用于肿瘤或炎症性病变的初步检测，或用于对患者进行分层 用于治疗癌症或关节炎的长循环纳米药物(如脂质体)的使用。