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Tissue macrophage numbers vary during health versus disease. Abundant inflammatory macrophages destruct tissues, leading to atherosclerosis, myocardial infarction and heart failure. Emerging therapeutic options create interest in monitoring macrophages in patients. Here we describe positron emission tomography (PET) imaging with 18F-Macroflor, a modified polyglucose nanoparticle with high avidity for macrophages. Due to its small size, Macroflor is excreted renally, a prerequisite for imaging with the isotope flourine-18. The particle's short blood half-life, measured in three species, including a primate, enables macrophage imaging in inflamed cardiovascular tissues. Macroflor enriches in cardiac and plaque macrophages, thereby increasing PET signal in murine infarcts and both mouse and rabbit atherosclerotic plaques. In PET/magnetic resonance imaging (MRI) experiments, Macroflor PET imaging detects changes in macrophage population size while molecular MRI reports on increasing or resolving inflammation. These data suggest that Macroflor PET/MRI could be a clinical tool to non-invasively monitor macrophage biology., Version of Record

Matrix metalloproteinases (MMPs) are involved in tissue remodeling. Accordingly, MMP inhibitors and related radiolabeled analogs are important tools for MMP-targeted imaging and therapy in a number of diseases. Herein, we report design, synthesis, and evaluation of a new Arginine-containing macrocyclic hydroxamate analog, RYM, its hydrazinonicotinamide conjugate, RYM1 and 99mTc-labeled analog 99mTc-RYM1 for molecular imaging. RYM exhibited potent inhibition against a panel of recombinant human (rh) MMPs in vitro. RYM1 was efficiently labeled with 99mTcO4− to give 99mTc-RYM1 in a high radiochemical yield and high radiochemical purity. RYM1 and its decayed labeling product displayed similar inhibition potencies against rhMMP-12. Furthermore, 99mTc-RYM1 exhibited specific binding with lung tissue from lung-specific interleukin-13 transgenic mice, in which MMP activity is increased in conjunction with tissue remodeling and inflammation. The results support further development of such new water-soluble Arginine-containing macrocyclic hydroxamate MMP inhibitors for targeted imaging and therapy. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) are widely implicated in cancer progression, and TAM levels can influence drug responses, particularly to immunotherapy and nanomedicines. However, it has been difficult to quantify total TAM numbers and their dynamic spatiotemporal distribution in a non-invasive and translationally relevant manner. Here, we address this need by developing a pharmacokinetically optimized, 64 Cu-labeled polyglucose nanoparticle (Macrin) for quantitative positron emission tomography (PET) imaging of macrophages in tumors. By combining PET with high-resolution in vivo confocal microscopy and ex vivo imaging of optically cleared tissue, we found that Macrin was taken up by macrophages with >90% selectivity. Uptake correlated with the content of macrophages in both healthy tissue and tumors ( R 2 > 0.9) and showed striking heterogeneity in the TAM content of an orthotopic and immunocompetent mouse model of lung carcinoma. In a proof-of-principle application, we imaged Macrin to monitor the macrophage response to neo-adjuvant therapy, using a panel of chemotherapeutic and γ-irradiation regimens. Multiple treatments elicited 180-650% increase in TAMs. Imaging identified especially TAM-rich tumors thought to exhibit enhanced permeability and retention of nanotherapeutics. Indeed, these TAM-rich tumors accumulated >700% higher amounts of a model poly(d,l-lactic- co-glycolic acid)- b-polyethylene glycol (PLGA-PEG) therapeutic nanoparticle compared to TAM-deficient tumors, suggesting that imaging may guide patient selection into nanomedicine trials. In an orthotopic breast cancer model, chemoradiation enhanced TAM and Macrin accumulation in tumors, which corresponded to the improved delivery and efficacy of two model nanotherapies, PEGylated liposomal doxorubicin and a TAM-targeted nanoformulation of the toll-like receptor 7/8 agonist resiquimod (R848). Thus, Macrin imaging offers a selective and translational means to quantify TAMs and inform therapeutic decisions.

Imaging techniques for detection of molecular and cellular processes that precede or accompany lung diseases are needed. Matrix metalloproteinases (MMPs) play key roles in the development of pulmonary pathology. The objective of this study was to investigate the feasibility of in vivo MMP-targeted molecular imaging for detection of lung inflammation and remodeling., Methods: Lung-specific IL-13 transgenic (Club cell 10-kDa protein [CC10]-IL-13 Tg) mice and wild-type littermates were used in this study. Lung structure, gene expression, and MMP activity were assessed by histology, real-time reverse transcription polymerase chain reaction, Western blotting, and zymography. MMP activation was imaged by in vivo small-animal SPECT/CT followed by ex vivo planar imaging. Signal specificity was addressed using a control tracer. The correlation between in vivo MMP signal and gene expression was addressed., Results: CC10-IL-13 Tg mice developed considerable pulmonary tissue remodeling and inflammation. CD68, MMP-12, and MMP-13 were significantly higher in CC10-IL-13 Tg lungs. On in vivo small-animal SPECT/CT and ex vivo planar images, the MMP signal was significantly higher in the lungs of CC10-IL-13 Tg mice than wild-type animals. Furthermore, a nonbinding analog tracer showed significantly lower accumulation in CC10-IL-13 Tg lungs relative to the specific tracer. There was a significant correlation between small-animal SPECT/CT-derived MMP signal and CD68 expression in the lungs (r = 0.70, P < 0.01)., Conclusion: Small-animal SPECT/CT-based MMP-targeted imaging of the lungs is feasible and reflects pulmonary inflammation. If validated in humans, molecular imaging of inflammation and remodeling can potentially help early diagnosis and monitoring of the effects of therapeutic interventions in pulmonary diseases., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Neurofibrillary tangles (NFTs) have long been recognized as one of the pathological hallmarks in Alzheimer's disease (AD). Recent studies, however, showed that soluble aggregated Tau species, especially hyperphosphorylated Tau oligomers, which are formed at early stage of AD prior to the formation of NFT, disrupted neural system integration. Unfortunately, little is known about Tau aggregates, and few Tau targeted imaging probe has been reported. Successful development of new imaging methods that can visualize early stages of Tau aggregation specifically will obviously be important for AD imaging, as well as understanding Tau-associated neuropathology of AD. Here, we report the first NIR ratiometric probe, CyDPA2, that targets Tau aggregates. The specificity of CyPDA2 to aggregated Tau was evaluated with in vitro hyperphosphorylated Tau proteins (pTau), as well as ex vivo Tau samples from AD human brain samples and the tauopathy transgenic mouse model, P301L. The characteristic enhancements of absorption ratio and fluorescence intensity in CyDPA2 were observed in a pTau concentration-dependent manner. In addition, fluorescence microscopy and gel staining studies demonstrated CyDPA2-labeled Tau aggregates. These data indicate that CyDPA2 is a promising imaging probe for studying Tau pathology and diagnosing AD at an early stage.