PEG-like Multimodal Nanoprobes for Imaging Enhanced Permeability Retention

描述（由申请人提供）：聚乙二醇样多模态纳米探针（PMN’s）是被动靶向纳米材料，用于确定通过增强渗透性和滞留性（EPR）获得的滞留机制，用于临床前EPR成像和建模，以及临床中EPR生物标志物的最终成像。EPR是长循环纳米药物（如药物-聚合物偶联物、脂质体）在肿瘤和炎症病变中的缓慢积累（注射后12-72小时）。PMN由DOTA、PEG和附着在（DOTA）Lys-Cys支架上的荧光染料组成。聚乙二醇提高了荧光染料的性能，并赋予PMN在生物系统中由聚乙二醇决定（而不是由荧光染料决定）的行为。PMN与其他EPR纳米探针（脂体、白蛋白、右转糖酐）的不同之处在于，即使PEG测定的PMN的尺寸超过肾小球滤过的尺寸限制，即使PMN表现出极其缓慢的全身清除，也能令人惊讶地在肾脏（而不是肝脏）消除EPR。PMN的荧光染料允许在组织（注射后显微镜）或培养细胞（FACS）中基于荧光的PMN测定，并将用于确定PMN保留的机制。DOTA允许111In3+放射性标记通过SPECT建模EPR，并最终通过SPECT或PET进行临床成像。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，以便使用用于治疗癌症或关节炎的长期循环纳米药物（如脂质体）。

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.