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Matrix metalloproteinase-initiated aggregation of melanin nanoparticles as highly efficient contrast agent for enhanced tumor accumulation and dual-modal imaging
Journal of Materials Chemistry B ( IF 7 ) Pub Date : 2020-08-31 , DOI: 10.1039/d0tb01651a
Tingwei Meng 1, 2, 3, 4, 5 , Bo Fan 3, 4, 5, 6 , Qian Li 3, 4, 5, 6 , Xiaoyang Peng 1, 2, 3, 4, 5 , Jun Xu 4, 5, 7 , Ruiping Zhang 4, 5, 8
Affiliation  

Ultrasmall melanin nanoparticles (MNPs) have great application potential in medical imaging, owing to its satisfactory biodegradation, intrinsic photoacoustic (PA) property and natural chelating ability with metal ions for magnetic resonance imaging (MRI). Because of its ultrasmall particle size, it was easily metabolized by the kidney, but had relatively limited tumor retention according to our previous study. To further improve the intensities of MRI and PA signals for precise diagnosis, it is vital to enhance its tumor accumulation and prolong the retention time. In this study, we developed a matrix metalloproteinase-2 (MMP-2) activatable nanoprobe (PEG-PepMMP2-MNP-Gd), which was composed of water-insoluble gadolinium-chelated melanin (MNP-Gd), MMP-2 cleaved peptide and enzymatic detachable polyethylene glycol (PEG). In the presence of MMP-2 activity, PEG-coating on the surface was peeled off and the “hidden” hydrophobic segment was then exposed, which initiated the aggregation and size increase of nanoprobes. We demonstrated that the hydrodynamic size of the MMP-2 activatable nanoprobe increased from 17.1 nm to 90.2 nm after in vitro incubation with MMP-2. Moreover, the in vivo T1-weighted MRI and PA signals in tumors were both dramatically enhanced and extended after the PEG-PepMMP2-MNP-Gd nanoparticles were intravenously injected into mice. This could be attributed to the changed size selectively activated by highly expressed MMP-2 in tumors, and allowing nanoparticles to possess higher tumor accumulation and longer retention. In short, MMP2-initiated size-changeable PEG-PepMMP2-MNP-Gd could meet the paradoxical demand for size-leading permeability and retention in solid tumors, suggesting its promising applications as a highly efficient MRI/PA contrast agent for precise tumor diagnosis.

中文翻译:

基质金属蛋白酶引发的黑色素纳米颗粒聚集体作为高效的造影剂,可增强肿瘤积累和双峰成像

超小黑色素纳米颗粒(MNP)由于其令人满意的生物降解,固有的光声(PA)特性以及与金属离子的天然螯合能力(用于磁共振成像(MRI)),在医学成像中具有巨大的应用潜力。由于其极小的粒径,根据我们先前的研究,它很容易被肾脏代谢,但其肿瘤保留相对有限。为了进一步改善MRI和PA信号的强度以进行精确诊断,至关重要的是增强其肿瘤积累并延长保留时间。在这项研究中,我们开发了一种基质金属蛋白酶2(MMP-2)激活的纳米探针(PEG-PepMMP2-MNP-Gd),该探针由水不溶性-螯合的黑色素(MNP-Gd),MMP-2裂解肽组成和可酶解的聚乙二醇(PEG)。在存在MMP-2活性的情况下,表面上的PEG涂层被剥落,然后暴露出“隐藏的”疏水链段,这引发了纳米探针的聚集和尺寸增大。我们证明了MMP-2可激活纳米探针的流体动力学尺寸从17.1 nm增加到90.2 nm与MMP-2体外孵育。此外,在将PEG-PepMMP2-MNP-Gd纳米颗粒静脉内注射入小鼠后,肿瘤中的体内T 1加权MRI和PA信号均显着增强和扩展。这可能归因于肿瘤中高表达的MMP-2选择性激活的大小改变,并允许纳米粒子拥有更高的肿瘤积累和更长的保留期。简而言之,MMP2引发的尺寸可变的PEG-PepMMP2-MNP-Gd可以满足对尺寸领先的实体肿瘤中的通透性和保留的悖论要求,这表明其作为用于精确肿瘤诊断的高效MRI / PA造影剂具有广阔的应用前景。
更新日期:2020-10-11
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