| BackgroundMagnetic Resonance Imaging?MRI?is a medical imaging technique used in the diagnosis of clinical diseases,which has developed rapidly in recent years.Among them,MRI contrast agents have become an indispensable part of this technology,mainly to shorten relaxation times of the local proton in vivo and speed up relaxation rate of the proton in water,which can enhance the signal contrast between normal and diseased tissue,and enhance the imaging effect.Therefore,the study of contrast agents with high relaxation,low toxicity and specificity has become the main trend of current development.Bacterial infections are an important cause of many diseases and deaths.The abuse of antibiotics has led to the emergence of a large number of drug-resistant bacteria.The diagnosis of bacterial infection has become the most direct and effective way to avoid the abuse of antibiotics.While it is difficult to distinguish bacterial inflammation from aseptic inflammation with the traditional detection methods.MRI technology has the characteristics of high sensitivity,low toxicity and noninvasiveness,which can effectively reduce the incidence of bacterial resistance and provide a detection platform and theoretical basis for detecting bacterial infection.To the best of our knowledge,there are few reports of bacterial MRI contrast agents.MRI contrast agents will be expected to open a new world for the diagnosis of bacterial infection.ObjectiveHerein,we reported two different classes of MRI control agents.One is the development of the fist gadolinium?Gd?-based bacteria-specific targeting MRI contrast agent.Another one is the nitroreductase-enhanced MRI contrast agent for bacteria imaging.Methods and Results1.In this study,we rationally design the first gadolinium?Gd?-based bacteria-specific targeting MRI contrast agent,Gd-DOTA-linker-Neo,by conjugating an aminoglycoside antibiotic,neomycin,with an FDA-approved T1-weighted MRI contrast agent,Gd-DOTA.The lipophilic linker is introduced into the probe molecule to improve the ability of cell membrane penetration of neomycin.The T1 relaxivity of Gd-DOTA-linker-Neo(r1=4.1mM–1s-1)was found to be comparable to that of clinical MRI contrast agent Gd-DOTA(r1=3.9 mM–1s-1);The relaxation rate R1,cell,cell of probe was about 10 times that of Gd-DOTA in S.aureus and about 5-fold that of Gd-DOTA in E.coli,but no imaging enhancement effect in normal cells;More importantly,a significant MRI signal enhancement was detected in the probe-prestained bacteria.Compared with Gd-DOTA-prestained bacteria,the signal intensities?SIs?increased 53%?***P<0.001?immediately after injection in mouse imaging,and the signal intensities decreased gradually within 4 hours,indicating its great potential for high-resolution imaging of bacterial infections in vivo.2.In this study,we have designed and synthesized a para-nitrobenzyl substituted T1-weighted magnetic resonance imaging?MRI?contrast agent?Gd-DOTA-PNB?.The Para-nitrobenzyl substituted probe was catalytically reduced by NTR to the intermediate para-aminobenzyl substituted probe,which then underwent a rearrangement elimination reaction to Gd-DOTA,generating the enhanced T1-weighted MR imaging.Compared with the probe(r1=3.1 mM–11 s-1),the r1 of Gd-DOTA was 3.1 mM–11 s-1,increased by 15%;More importantly,MR images studies of living E.coli and hypoxic tumor cells incubated with probe resulted an 8%signal intensity enhancement,which indicates that probe could serve as a MRI-enhanced contrast agent for monitoring NTR activity.ConclusionIn this paper,two kinds of bacterial-specific MRI probes were firstly synthesized.The targeted probe had better targeting effect on bacteria,and different degrees of imaging enhancement to Gram-positive and Gram-negative bacteria,which could be used as a potential bacterial infection diagnostic agent;The enzyme-activated probe had a certain imaging enhancement effect and could be used to detect the activity of NTR in bacteria,providing a basis for the diagnosis of bacterial infection. |
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