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Radiolabeled Cationic Peptides for Targeted Imaging of Infection
Tolulope A Aweda1, Zumrut F B Muftuler2, Adriana V F Massicano1
1Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA.
Abstract:
Molecular probes targeting bacteria provide opportunities to target bacterial infections in vivo for both imaging and therapy. In the current study, we report the development of positron emission tomography (PET) probes for imaging of live bacterial infection based on the small molecules HLys-DOTA, a polycationic peptide synthesized as the D-isomer (RYWVAWRNRG) conjugated to 1, 4, 7, 10-tetraazacyclododecane-N',N″,N‴,N-tetraacetic acid (DOTA) and AB1-HLys-DOTA, which includes an unnatural amino acid AB1 that preferentially binds to bacteria membrane lipids with amine groups via formation of iminoboronates. HLys-DOTA and AB1-HLys-DOTA peptides were radiolabeled with 64Cu and investigated as PET imaging agents to track bacterial infection in vitro and in intramuscularly infected (IM) mice models. Cell uptake studies at 37°C in Staphylococcus aureus (SA) show higher uptake of 64Cu-AB1-HLys-DOTA; 98.47 ± 3.54% vs 64Cu-HLys-DOTA; 39.12 ± 3.27% at 24 h. Standard uptake values (SUV) analysis of the PET images resulted in mean SUV of 0.70 ± 0.08, 0.49 ± 0.04, and 0.31 ± 0.01 for 64Cu-AB1-HLys-DOTA and 0.17 ± 0.06, 0.16 ± 0.02, and 0.13 ± 0.01 for 64Cu-HLys-DOTA at 1, 4, and 24 h post injection, respectively, in the infected muscles. Similarly, in the biodistribution studies, dose uptake in the infected muscles was 4 times higher in the targeted 64Cu-AB1-HLys-DOTA group than in the 64Cu-HLys-DOTA group and 2-3 times higher than in the PBS control group at 1, 4, and 24 h post injection. 64Cu-AB1-HLys-DOTA was able to distinguish between SA-infected muscle and Pseudomonas aeruginosa (PA) infected muscle with lower mean SUV of 0.28 ± 0.10 at 1 h post injection. This illustrates the utility of the AB1 covalently targeting group in synergy with the HLys peptide, which noncovalently binds to bacterial membranes. These results suggest that 64Cu-labeled AB1-HLys-DOTA peptide could be used as an imaging probe for detection of bacterial infection in vivo with specificity for Gram-positive bacteria.
Insights
Researchers developed novel positron emission tomography (PET) probes, AB1-HLys-DOTA, for imaging bacterial infections. These probes show high uptake in Staphylococcus aureus infections, enabling effective in vivo detection.
Area of Science:
- Molecular imaging
- Radiochemistry
- Infectious disease diagnostics
Background:
- Bacterial infections pose significant health challenges, necessitating advanced diagnostic tools.
- Molecular probes offer potential for in vivo imaging and therapy of bacterial infections.
Purpose of the Study:
- To develop and evaluate novel positron emission tomography (PET) probes for detecting bacterial infections in vivo.
- To assess the efficacy of 64Cu-labeled AB1-HLys-DOTA and 64Cu-HLys-DOTA as PET imaging agents.
Main Methods:
- Synthesis and radiolabeling of HLys-DOTA and AB1-HLys-DOTA peptides with 64Cu.
- In vitro cell uptake studies using Staphylococcus aureus (SA).
- In vivo PET imaging and biodistribution studies in intramuscularly infected mice models.
Main Results:
- 64Cu-AB1-HLys-DOTA demonstrated significantly higher cell uptake (98.47%) compared to 64Cu-HLys-DOTA (39.12%) in SA at 24 hours.
- In vivo studies showed 4-fold higher uptake of 64Cu-AB1-HLys-DOTA in infected muscles compared to 64Cu-HLys-DOTA.
- The probe successfully distinguished between SA-infected and Pseudomonas aeruginosa-infected muscle.
Conclusions:
- 64Cu-labeled AB1-HLys-DOTA is a promising PET imaging probe for detecting bacterial infections in vivo.
- The AB1 targeting group enhances probe accumulation in infected tissues, offering specificity for Gram-positive bacteria.
