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Published on: May 8, 2017
An activatable Mn(II) MRI probe for detecting peroxidase activity in vitro and in vivo
Yunhe Li1, Qian Xia2, Chunrong Zhu2
1Sichuan Key Laboratory of Medical Imaging, Department of Oncology, and Department of Pharmacy, Affiliated Hospital of North Sichuan Medical College, Maoyuan Road 1, Nanchong City, Sichuan 637000, China; School of Pharmacy, North Sichuan Medical College, Fujiang Road 234, Nanchong City, Sichuan 637000, China.
Abstract:
Myeloperoxidase (MPO), a hallmark of the function and activation of innate immune cells, can act as a 'double-edged sword', contributing to clear infection as well as causing tissue oxidizing damage in various inflammatory diseases. In this study, an activatable Mn(II) chelate-based magnetic resonance imaging (MRI) contrast agent (CA), Mn-TyEDTA (TyEDTA = tyrosine derived ethylenediaminetetraacetic acid) structurally featuring a phenol group as the electron-donor, was developed to sense the activity of peroxidase in vitro and in vivo. Mn-TyEDTA demonstrated a peroxidase activity-dependent relaxivity in the presence of horseradish peroxidase (HRP)/H2O2 with more than a 2.6-fold increase in water proton relaxivity produced (HRP, 500 U; H2O2, 4.5 eq). A mechanism of peroxidase-mediated Mn(II) monomer radical polymerization was confirmed with those oligomers of Mn-TyEDTA such as dimer, trimer and tetramer were found in the LC-MS study. Dynamic MR imaging of normal mice revealed rapid blood clearance and mixed renal and hepatobiliary elimination of Mn-TyEDTA. Furthermore, compared to liver-specific and non-specific extracellular contrast agents (Mn-BnO-TyEDTA (BnO-TyEDTA = benzyl tyrosine-derived ethylenediaminetetraacetic acid) and Gd-DTPA (DTPA = diethylene triamine penta-acetic acid)), MRI on a monosodium urate (MSU) crystal-induced acute mice model of arthritis showed that inflamed tissues could be selectively enhanced by Mn-TyEDTA, suggesting that this peroxidase-activatable Mn(II) MRI probe could potentially be used for noninvasive detection of MPO activity in vivo.
Insights
A novel manganese (Mn(II)) MRI contrast agent, Mn-TyEDTA, was developed to detect peroxidase activity. This agent selectively enhances inflamed tissues in arthritis models, offering a new tool for diagnosing inflammatory diseases.
Area of Science:
- Biomedical Imaging
- Chemical Biology
- Materials Science
Background:
- Myeloperoxidase (MPO) is crucial in innate immunity but also implicated in inflammatory tissue damage.
- Existing MRI contrast agents lack specificity for detecting MPO activity in inflammatory conditions.
Purpose of the Study:
- Develop an activatable Mn(II) chelate-based MRI contrast agent (CA) for sensing peroxidase activity.
- Evaluate the agent's performance in vitro and in vivo for detecting inflammation.
Main Methods:
- Synthesized Mn-TyEDTA, a tyrosine-derived ethylenediaminetetraacetic acid chelate with a phenol group.
- Assessed Mn-TyEDTA relaxivity changes in response to horseradish peroxidase (HRP)/H2O2.
- Investigated the reaction mechanism using LC-MS to identify Mn-TyEDTA oligomers.
- Performed dynamic MRI in normal mice to determine blood clearance and elimination pathways.
- Compared Mn-TyEDTA with Gd-DTPA and Mn-BnO-TyEDTA in a monosodium urate (MSU) crystal-induced arthritis mouse model.
Main Results:
- Mn-TyEDTA exhibited a >2.6-fold increase in water proton relaxivity dependent on peroxidase activity.
- Peroxidase-mediated Mn(II) radical polymerization mechanism was confirmed, forming dimers, trimers, and tetramers.
- Dynamic MRI showed rapid blood clearance and mixed renal/hepatobiliary elimination in mice.
- In vivo MRI demonstrated selective enhancement of inflamed tissues in an arthritis model.
Conclusions:
- Mn-TyEDTA is a novel peroxidase-activatable Mn(II) MRI contrast agent.
- The agent shows potential for noninvasive detection of MPO activity in inflammatory diseases.
- This probe offers improved diagnostic capabilities compared to existing MRI contrast agents.
