PEG-like Multimodal Nanoprobes for Imaging Enhanced Permeability Retention

摘要 PEG样多模态纳米探针（PMN）是被动靶向的纳米材料，用于确定 通过增强渗透性和保留（EPR）获得的保留机制，用于成像和建模 临床前EPR，以及临床中EPR生物标志物的最终成像。EPR是缓慢的 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作用。PMN由DOTA、PEG和荧光染料组成， 连接到（DOTA）Lys-Cys支架。PEG改善荧光染料性能并赋予PMN PEG- 确定（而不是荧光染料确定）生物系统中的行为。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（而不是肝）消除， 即使当PEG确定的PMN的尺寸超过肾小球滤过的尺寸限制时， 当PMN表现出大量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中的PMN（注射后显微镜检查），或 培养的细胞（FACS），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对EPR建模和用于通过SPECT或PET的最终临床成像。PMN-EPR 成像可用于肿瘤或炎性病变的初步检测，或用于对患者进行分层， 使用长循环纳米药物（例如脂质体）治疗他们的癌症或关节炎。

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.