Evaluation of [68Ga]Ga-DOTA-AeK as a Potential Imaging Tool for PET Imaging of Cell Wall Synthesis in Bacterial Infections
Abstract
:1. Introduction
2. Results and Discussion
2.1. Development of 68Ga Radiolabeling Method for DOTA-AeK
2.1.1. Effects of Radiolabeling Conditions on Ga-68-Complexation of DOTA-AeK
2.1.2. Ga-68-Eluate Acidity and Vector Concentration (DOTA-AeK)
2.1.3. Optimization of Incubation Parameters
2.2. Development of a Purification Method of [68Ga]Ga-DOTA-AeK
2.3. Log P Determination for [68Ga]Ga-DOTA-AeK
2.4. Serum Protein Binding of [68Ga]Ga-DOTA-AeK and Proteolytic Stability
2.5. Formulation Stability
2.6. Bacterial Cell Uptake of [68Ga]Ga-DOTA-AeK
2.7. Exploratory Biodistribution of [68Ga]Ga-DOTA-AeK
PET/CT Imaging and Ex Vivo Biodistribution
3. Materials and Methods
3.1. Testing Radioanalytical Methods for [68Ga]Ga-DOTA-AeK Quality Control
3.2. Development of a Radiosynthesis Method for [68Ga]Ga-DOTA-AeK
3.3. Optimization of a Purification Technique for [68Ga]Ga-DOTA-AeK
3.4. Radiochemical and Thermodynamical Stability
3.5. Log P Determination
3.6. Proteolytic Stability and Serum Protein Binding of [68Ga]Ga-DOTA-AeK
3.7. Bacterial Cell Uptake of [68Ga]Ga-DOTA-AeK
3.8. Bacterial Cell Uptake and Incorporation of AeK-NBD
3.8.1. Flow Cytometry
3.8.2. Confocal Microscopy
3.9. Exploratory [68Ga]Ga-DOTA-AeK-PET/CT Imaging
3.9.1. Animals
3.9.2. Establishment of the Murine Infection and Inflammation Animal Model
3.9.3. Animal Imaging Procedure
3.9.4. Ex Vivo Biodistribution Studies and Histopathology
3.10. Statistical Analysis
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AeK | L-Ala-γ-D-Glu-L-Lys |
CFU | Colony Forming Units |
CT | Computed Tomography |
DOTA | 4,7,10 tetraaza-cyclododecane-N,N′,N″,N‴-tetraacetic acid |
E. coli | Escherichia coli |
HLB | Hydrophilic–lipophilic balance |
HPLC | High-performance liquid chromatography |
%ID/g | Percentage of injected dose per gram organ |
ITLC | Instant thin-layer chromatography |
IVC | Individually ventilated cages |
MFI | Median fluorescence intensity |
MRI | Magnetic resonance imaging |
NBD | N-7-nitro-2,1,3-benzoxadiazol-4-yl |
Opp | Oligopeptide permease |
PBS | Phosphate-buffered saline |
PET | Positron emission tomography |
PG | Peptidoglycan |
Rf | Retention factors |
Rs | Resolution |
RCP | Radiochemical purity |
S. aureus | Staphylococcus aureus |
SD | Standard deviation |
SPE | Solid-phase extraction |
TSB | Tryptic soy broth |
UDP-MurNAc | Uridine diphosphate -N-acetylmuramic acid |
VDC | Vybrant DyeCycle |
Appendix A. Supplementary Data
Appendix A.1. Material
General Information
Appendix A.2. Results
Appendix A.2.1. Testing of Radioanalytical Methods for [68Ga]Ga-DOTA-AeK Quality Control
HPLC and LC/MS
ITLC
Mobile Phase A | Mobile Phase B | |||
---|---|---|---|---|
[68Ga]Ga-DOTA-AeK | [68Ga]GaCl3 (Ionic + Colloidal) | [68Ga]Ga-DOTA-AeK | [68Ga]GaCl3 (Ionic + Colloidal) | |
Rf | 0.2 | 0.7 | 0.7 | 0.1 |
Rs | 1.6 | 1.1 |
Appendix A.2.2. Development of a Purification Method of [68Ga]Ga-DOTA-AeK
Cartridge-Absorbent | Conditioning (Volume/Agent) | Activity Retention (%LA) | Wash and Rinse (Volume/Agent) | Activity Retention (%LA) Post-Wash | Activity Elution (Volume/Agent) | Recovery Efficiency (%RA) | %RCP |
---|---|---|---|---|---|---|---|
(A) C-18 145 mg | 4 mL EtOH + 2 mL H2O | 72.8 | 1 mL H2O | - | 1 mL 50% v/v EtOH * | 37.3 | 39.9 |
4 mL EtOH + 2 mL H2O | 92.6 | 1 mL Saline | 60 | 1 mL 50% v/v EtOH ** | 46.2 | 11.8 | |
4 mL EtOH + 2 mL H2O | 89.2 | 1 mL PBS | 55.7 | 1 mL 50% v/v EtOH * | 41.6 | 11.9 | |
(B) C-8 145 mg | 3 mL EtOH + 3 mL H2O | 83.8 | 1 mL Saline | 32.5 | 1 mL 100% v/v EtOH | 19.4 | 12.6 |
(C) HBL 200 mg | 1 mL EtOH + 1 mL H2O | 42.4 | 1 mL H2O | - | 1 mL 100% v/v EtOH | 5.5 | 11.2 |
(D) Strata X 100 mg | 4 mL EtOH + 2 mL H2O | 63.6 | 1 mL H2O | 7.5 | 1 mL 100% v/v EtOH | 6.1 | 19.7 |
(A–A) C-18 290 mg | 10 mL EtOH + 10 mL H2O | 98.4 | 1 mL 50% EtOH * | 35.2 | 1 mL50% v/v EtOH * | 29.1 | 15.3 |
10 mL EtOH + 10 mL H2O (n = 9) | 99.7 ± 0.2 | 1 mL PBS | 85.8 ± 6.9 | 1 mL 5% v/v EtOH ** | 60.7 ± 12.7 | 100 | |
10 mL EtOH + 10 mL H2O | 99.4 | 0.4 mL H2O | 93.8 | 1 mL 10% v/v EtOH * | 78.3 | 39.9 | |
10 mL EtOH + 10 mL H2O (n = 6) | 99.8 ± 0.1 | 0.4 mL PBS | 94.9 ± 6.2 | 1 mL 5% v/v EtOH ** | 83.5 ± 7.6 | 100 |
Appendix A.2.3. Confocal Imaging
Appendix A.2.4. [68Ga]Ga-DOTA-AeK- Ex Vivo Biodistribution
Post-Inoculation | E. coli | S. aureus | ||||
---|---|---|---|---|---|---|
Day 3 (n = 4) | Day 5 (n = 4) | * p-Value | Day 3 (n = 5) | Day 5 (n = 3) | * p-Value | |
Brain | 0.1 ± 0.0 | 0.2 ± 0.2 | 0.344 | 0.1 ± 0.0 | 0.2 ± 0.0 | 0.030 |
Thyroid | 1.0 ± 0.7 | 0.7 ± 0.3 | 0.497 | 0.9 ± 0.5 | 1.9 ± 0.3 | 0.020 |
Heart | 0.8 ± 0.4 | 1.6 ± 1.3 | 0.299 | 1.2 ± 0.3 | 3.7 ± 0.5 | 0.000 |
Lungs | 1.0 ± 0.1 | 2.0 ± 0.4 | 0.003 | 1.8 ± 0.5 | 3.7 ± 0.5 | 0.002 |
Liver | 1.1 ± 0.2 | 1.2 ± 0.4 | 0.631 | 1.5 ± 0.5 | 3.6 ± 1.5 | 0.024 |
Spleen | 0.7 ± 0.3 | 0.7 ± 0.1 | 0.986 | 1.4 ± 1.6 | 1.6 ± 0.6 | 0.801 |
Pancreas | 0.6 ± 0.3 | 0.8 ± 0.4 | 0.450 | 0.7 ± 0.3 | 2.3 ± 0.2 | 0.000 |
Stomach | 0.3 ± 0.1 | 1.3 ± 1.8 | 0.295 | 0.7 ± 0.5 | 1.1 ± 0.4 | 0.347 |
Intestines | 0.4 ± 0.2 | 1.1 ± 1.2 | 0.356 | 1.2 ± 1.9 | 1.8 ± 0.8 | 0.653 |
Kidneys | 3.8 ± 1.6 | 2.9 ± 0.7 | 0.374 | 5.6 ± 3.4 | 7.0 ± 0.1 | 0.512 |
Adipose | 0.7 ± 0.1 | 0.8 ± 0.7 | 0.459 | 1.0 ± 0.4 | 1.9 ± 0.3 | 0.010 |
Femur | 1.4 ± 1.0 | 0.9 ± 0.4 | 0.453 | 1.2 ± 1.3 | 2.0 ± 0.2 | 0.335 |
Muscle | 0.7 ± 0.4 | 0.6 ± 0.2 | 0.632 | 0.4 ± 0.4 | 1.1 ± 0.5 | 0.041 |
Inflammation | 0.9 ± 0.0 | 0.9 ± 0.1 | 0.987 | 1.1 ± 0.5 | 2.6 ± 0.6 | 0.010 |
Infection | 0.4 ± 0.1 | 0.4 ± 0.0 | 0.398 | 0.8 ± 0.6 | 0.9 ± 0.3 | 0.781 |
Inflammation/muscle | 2.0 ± 1.6 | 1.8 ± 0.8 | 0.492 | 7.1 ± 9.9 | 2.1 ± 0.3 | 0.064 |
Infection/muscle | 0.8 ± 0.5 | 0.8 ± 0.3 | 0.771 | 3.0 ± 0.2 | 0.8 ± 0.1 | 0.559 |
Appendix A.2.5. Histopathology
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Treatment (Wash & Rinse) | Activity Retention (%LA) | Activity Retention (%LA) Post-Wash | Recovery Efficiency (%RA) | RCP (%) |
---|---|---|---|---|
1 mL PBS (n = 9) | 99.7 ± 0.2 | 85.8 ± 6.9 | 60.7 ± 12.7 | 100 |
0.4 mL PBS (n = 6) | 99.8 ± 0.1 | 94.9 ± 6.2 | 83.5 ± 7.6 | 100 |
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Koatale, P.C.; Welling, M.M.; Mdanda, S.; Mdlophane, A.; Takyi-Williams, J.; Durandt, C.; van den Bout, I.; Cleeren, F.; Sathekge, M.M.; Ebenhan, T. Evaluation of [68Ga]Ga-DOTA-AeK as a Potential Imaging Tool for PET Imaging of Cell Wall Synthesis in Bacterial Infections. Pharmaceuticals 2024, 17, 1150. https://doi.org/10.3390/ph17091150
Koatale PC, Welling MM, Mdanda S, Mdlophane A, Takyi-Williams J, Durandt C, van den Bout I, Cleeren F, Sathekge MM, Ebenhan T. Evaluation of [68Ga]Ga-DOTA-AeK as a Potential Imaging Tool for PET Imaging of Cell Wall Synthesis in Bacterial Infections. Pharmaceuticals. 2024; 17(9):1150. https://doi.org/10.3390/ph17091150
Chicago/Turabian StyleKoatale, Palesa C., Mick M. Welling, Sipho Mdanda, Amanda Mdlophane, John Takyi-Williams, Chrisna Durandt, Iman van den Bout, Frederik Cleeren, Mike M. Sathekge, and Thomas Ebenhan. 2024. "Evaluation of [68Ga]Ga-DOTA-AeK as a Potential Imaging Tool for PET Imaging of Cell Wall Synthesis in Bacterial Infections" Pharmaceuticals 17, no. 9: 1150. https://doi.org/10.3390/ph17091150