Impact of Different [Tc(N)PNP]-Scaffolds on the Biological Properties of the Small cRGDfK Peptide: Synthesis, In Vitro and In Vivo Evaluations
Abstract
:1. Introduction
2. Results
2.1. Peptide Synthesis
2.2. Radiosyntheses
2.3. Cell Studies
2.4. Metabolism and In Vivo Studies
2.4.1. In Vitro Metabolism
2.4.2. In Vivo Studies
3. Discussion
4. Materials and Methods
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
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Complex | HPLC Rt min | a/b | %RCY | % Protein Binding * | Log P | ||
---|---|---|---|---|---|---|---|
H3NS-cRGDfK | 13.00 1 | ||||||
[Tc(N)(H2NS-cRGDfK)(PNP3)]+ | 99mTc1 | a | 14.09 1; 11.39 2 | 61.76/31.98 | 93.74 ± 0.05 | 14.95 ± 1.95 | −1.72 1 |
b | 15.79 1; 13.23 2 | ||||||
[Tc(N)(H2NS-cRGDfK)(PNP43)]+ | 99mTc2 | a | 12.78 2; 26.04 3 | 60.64/27.80 | 89.04 ± 0.09 | 13.63 ± 2.95 | −1.95 |
b | 15.45 2; 29.08 3 | ||||||
[Tc(N)(H2NS-cRGDfK)(PNP3OH)]+ | 99mTc3 | a | 8.21 2; 22.75 3 | 67.56/23.33 | 90.89 ± 0.11 | 7.91 ± 2.01 | −2.39 |
b | 10.12 2; 24.86 3 | ||||||
[Tc-HYNIC-cRGDfK] | 9.02 2 | 2.3 ± 0.11 | −3.52 |
Cell Line (Tumor Type) | ΔMFI αvβ3 | αvβ3 | ΔMFI αvβ5 | αvβ5 |
---|---|---|---|---|
M21 (Human melanoma) | 25 | +++ | 1 | ---- |
MCF7 (Human breast cancer) | 4 | ---- | 67 | ++++ |
M21-L (Human melanoma) | 1 | ---- | 0 | ---- |
Range for MFI values of αvβ3 | Range for MFI values of αvβ5 | |||
| |
99mTc1 | 99mTc2 | 99mTc3 | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Organs | 30 min | 60 min | 120 min | 240 min | 30 min | 60 min | 120 min | 240 min | 30 min | 60 min | 120 min | 240 min |
Blood | 0.81 ± 0.05 | 0.30 ± 0.04 | 0.09 ± 0.01 | 0.05 ± 0.01 | 0.65 ± 0.04 | 0.35 ± 0.07 | 0.19 ± 0.04 | 0.11 ± 0.02 | 0.46 ± 0.07 | 0.25 ± 0.03 | 0.16 ± 0.01 | 0.09 ± 0.01 |
Heart | 0.26 ± 0.05 | 0.15 ± 0.01 | 0.10 ± 0.02 | 0.08 ± 0.01 | 0.30 ± 0.01 | 0.20 ± 0.04 | 0.15 ± 0.06 | 0.12 ± 0.01 | 0.25 ± 0.06 | 0.15 ± 0.00 | 0.13 ± 0.02 | 0.12 ± 0.03 |
Lungs | 0.64 ± 0.09 | 0.43 ± 0.01 | 0.25 ± 0.03 | 0.16 ± 0.04 | 0.82 ± 0.09 | 0.56 ± 0.10 | 0.42 ± 0.02 | 0.34 ± 0.04 | 0.62 ± 0.08 | 0.49 ± 0.01 | 0.37 ± 0.06 | 0.32 ± 0.02 |
Liver | 0.96 ± 0.10 | 0.75 ± 0.02 | 0.68 ± 0.06 | 0.66 ± 0.07 | 0.90 ± 0.13 | 0.73 ± 0.01 | 0.57 ± 0.03 | 0.52 ± 0.07 | 0.90 ± 0.09 | 0.80 ± 0.06 | 0.75 ± 0.09 | 0.67 ± 0.04 |
Spleen | 0.65 ± 0.09 | 0.51 ± 0.04 | 0.47 ± 0.04 | 0.45 ± 0.00 | 0.47 ± 0.02 | 0.40 ± 0.05 | 0.38 ± 0.04 | 0.34 ± 0.07 | 0.43 ± 0.05 | 0.39 ± 0.04 | 0.36 ± 0.02 | 0.34 ± 0.04 |
Kidneys | 2.71 ± 0.18 | 1.57 ± 0.13 | 0.92 ± 0.20 | 0.88 ± 0.09 | 6.77 ± 0.86 | 6.20 ± 0.68 | 5.51 ± 0.42 | 4.27 ± 0.31 | 5.22 ± 0.44 | 4.83 ± 0.35 | 4.44 ± 0.32 | 4.22 ± 0.45 |
Stomach | 0.53 ± 0.07 | 0.41 ± 0.02 | 0.34 ± 0.04 | 0.29 ± 0.02 | 0.82 ± 0.07 | 0.64 ± 0.08 | 0.51 ± 0.08 | 0.41 ± 0.09 | 0.72 ± 0.04 | 0.64 ± 0.08 | 0.57 ± 0.03 | 0.46 ± 0.04 |
Intestine | 0.65 ± 0.16 | 0.60 ± 0.12 | 0.40 ± 0.07 | 0.38 ± 0.01 | 1.19 ± 0.14 | 1.69 ± 0.17 | 1.94 ± 0.25 | 1.90 ± 0.19 | 1.29 ± 0.13 | 1.95 ± 0.17 | 3.76 ± 0.27 | 4.17 ± 0.59 |
Muscle | 0.21 ± 0.09 | 0.13 ± 0.06 | 0.10 ± 0.06 | 0.06 ± 0.01 | 0.22 ± 0.03 | 0.14 ± 0.03 | 0.12 ± 0.01 | 0.09 ± 0.00 | 0.17 ± 0.01 | 0.13 ± 0.01 | 0.12 ± 0.00 | 0.08 ± 0.00 |
Urine | 27.2 ± 11.7 | 33.1 ± 5.6 | 54.3 ± 1.9 | 55.9 ± 7.1 | 17.7 ± 3.6 | 28.5 ± 4.6 | 41.5 ± 4.5 | 43.5 ± 3.4 | 27.8 ± 5.6 | 31.2 ± 3.0 | 44.2 ± 10.9 | 30.2 ± 9.45 |
Organ | MRT (min) | ||
---|---|---|---|
99mTc1 | 99mTc2 | 99mTc3 | |
Blood | 14.7 | 16.9 | 14.5 |
Heart | 0.3 | 0.4 | 0.4 |
Lung | 0.9 | 1.6 | 1.6 |
Liver | 30.5 | 25.9 | 26.7 |
Kidney | 9.2 | 30.7 | 36.7 |
Spleen | 1.2 | 0.8 | 0.8 |
Stomach | 1.5 | 2.1 | 2.1 |
Organs | 99mTc1 | 99mTc2 | 99mTc3 | 99mTc_HYNIC [40] | |
---|---|---|---|---|---|
1 h | 4 h | ||||
Blood | 0.07 ± 0.02 | 0.12 ± 0.03 | 0.05 ± 0.01 | 0.98 ± 0.04 | 0.45 ± 0.02 |
Heart | 0.47 ± 0.03 | 0.48 ± 0.07 | 0.44 ± 0.09 | 1.01 ± 0.05 | 0.64 ± 0.09 |
Lungs | 1.25 ± 0.23 | 1.04 ± 0.08 | 1.32 ± 0.20 | ||
Liver | 3.59 ± 0.31 | 2.43 ± 0.23 | 3.22 ± 0.24 | 2.63 ± 0.14 | 1.71 ± 0.28 |
Spleen | 1.61 ± 0.01 | 1.26 ± 0.04 | 1.43 ± 0.19 | ||
Kidneys | 4.10 ± 0.37 | 3.38 ± 0.36 | 3.34 ± 0.18 | 3.68 ± 0.13 | 2.81 ± 0.37 |
Stomach * | 1.22 ± 0.15 | 1.02 ± 0.16 | 1.05 ± 0.14 | 2.50 ± 0.75 | 1.28 ± 0.22 |
Intestine | 2.30 ± 0.10 | 2.45 ± 0.29 | 3.09 ± 0.62 | 2.04 ± 0.18 | 1.29 ± 0.25 |
Muscle | 0.37 ± 0.04 | 0.31 ± 0.05 | 0.23 ± 0.03 | 0.76 ± 0.69 | 0.34 ± 0.05 |
M21 | 3.17 ± 0.60 | 1.08 ± 0.24 | 3.92 ± 0.69 | 2.73 ± 0.26 | 2.06 ± 0.37 |
M21L | 1.73 ± 0.19 | 0.42 ± 0.05 | 0.70 ± 0.16 | 0.85 ± 0.20 | |
M21/M21L | 1.83 | 2.57 | 5.60 | 3.21 | |
M21/blood | 29.96 | 11.26 | 73.42 | 2.79 | 4.58 |
M21/muscle | 9.15 | 3.54 | 16.72 | 3.59 | 6.05 |
M21/liver | 0.88 | 0.44 | 1.11 | 1.03 | 1.20 |
M21/lung | 2.53 | 1.04 | 2.98 | ||
M21/kidneys | 0.77 | 0.32 | 1.23 | 0.74 | 0.73 |
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Salvarese, N.; Carpanese, D.; Meléndez-Alafort, L.; De Nardo, L.; Calderan, A.; Biondi, B.; Ruzza, P.; Rosato, A.; Bolzati, C. Impact of Different [Tc(N)PNP]-Scaffolds on the Biological Properties of the Small cRGDfK Peptide: Synthesis, In Vitro and In Vivo Evaluations. Molecules 2022, 27, 2548. https://doi.org/10.3390/molecules27082548
Salvarese N, Carpanese D, Meléndez-Alafort L, De Nardo L, Calderan A, Biondi B, Ruzza P, Rosato A, Bolzati C. Impact of Different [Tc(N)PNP]-Scaffolds on the Biological Properties of the Small cRGDfK Peptide: Synthesis, In Vitro and In Vivo Evaluations. Molecules. 2022; 27(8):2548. https://doi.org/10.3390/molecules27082548
Chicago/Turabian StyleSalvarese, Nicola, Debora Carpanese, Laura Meléndez-Alafort, Laura De Nardo, Andrea Calderan, Barbara Biondi, Paolo Ruzza, Antonio Rosato, and Cristina Bolzati. 2022. "Impact of Different [Tc(N)PNP]-Scaffolds on the Biological Properties of the Small cRGDfK Peptide: Synthesis, In Vitro and In Vivo Evaluations" Molecules 27, no. 8: 2548. https://doi.org/10.3390/molecules27082548