Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. A Prodrug Strategy Is Crucial for Antitumor Activity
2.1.1. Binding Affinity of PSMA-Targeted MMAE-Cy5.5 Conjugates
2.1.2. Cathepsin Cleavage of PSMA-Targeted MMAE-Cy5.5 Conjugates
2.1.3. Cellular Uptake Studies
2.1.4. Disruption of α-Tubulin
2.1.5. In Vitro Cytotoxicity of PSMA-Targeted MMAE-Cy5.5 Conjugates
2.1.6. In Vivo Fluorescence Imaging of PSMA-Targeted MMAE-Cy5.5 Conjugates
2.1.7. In Vivo Antitumor Activity of PSMA-Targeted MMAE-Cy5.5 Conjugates
2.2. Efficacy of PSMA-1-VcMMAE
2.2.1. In Vitro Characterization of PSMA-1-VcMMAE
2.2.2. Maximum Tolerated Dose of PSMA-1-VcMMAE
2.2.3. In Vivo Antitumor Activity of PSMA-1-VcMMAE
3. Discussion
4. Materials and Methods
4.1. General
4.2. Synthesis of PSMA-Targeting MMAE Conjugates
4.2.1. Synthesis of PSMA-1-VcMMAE
4.2.2. Synthesis of PSMA-1-VcMMAE-Cy5.5
4.2.3. Synthesis of PSMA-1-McMMAE-Cy5.5
4.3. Cell Culture
4.4. Competitive Binding Assay
4.5. Enzymatic Cleavage of PSMA-1-MMAE-Cy5.5 by Cathepsin B
4.6. In Vitro Cellular Uptake Studies
4.7. Immunofluorescence Analysis of Alpha-Tubulin
4.8. In Vitro Cytotoxicity Assay
4.9. In Vivo NIR Imaging Studies
4.10. Determination of Maximum Tolerated Dose (MTD)
4.11. Heterotopic Survival Study
4.12. Orthotopic Survival Study
4.13. Metastatic Survival Study
4.14. Statistics
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cells | PSMA-1-VcMMAE (EC50, nM) | PSMA-1-VcMMAE + PSMA-1 (EC50, nM) | PSMA-1-VcMMAE + E64 (EC50, nM) | MMAE (EC50, nM) | PSMA-ADC (EC50, nM) |
---|---|---|---|---|---|
PC3pip | 4.64 ± 0.83 | 241.1 ± 8.6 | 31.09 ± 2.11 | 0.24 ± 0.05 | 0.063 ± 0.003 |
PC3flu | 221.7 ± 2.8 | 261.3 ± 5.6 | 384.9 ± 5.3 | 0.21 ± 0.04 | 241.8 ± 9.3 |
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Wang, X.; Shirke, A.; Walker, E.; Sun, R.; Ramamurthy, G.; Wang, J.; Shan, L.; Mangadlao, J.; Dong, Z.; Li, J.; et al. Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer. Cancers 2021, 13, 417. https://doi.org/10.3390/cancers13030417
Wang X, Shirke A, Walker E, Sun R, Ramamurthy G, Wang J, Shan L, Mangadlao J, Dong Z, Li J, et al. Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer. Cancers. 2021; 13(3):417. https://doi.org/10.3390/cancers13030417
Chicago/Turabian StyleWang, Xinning, Aditi Shirke, Ethan Walker, Rongcan Sun, Gopolakrishnan Ramamurthy, Jing Wang, Lingpeng Shan, Joey Mangadlao, Zhipeng Dong, Jing Li, and et al. 2021. "Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer" Cancers 13, no. 3: 417. https://doi.org/10.3390/cancers13030417
APA StyleWang, X., Shirke, A., Walker, E., Sun, R., Ramamurthy, G., Wang, J., Shan, L., Mangadlao, J., Dong, Z., Li, J., Wang, Z., Schluchter, M., Luo, D., Wang, Y., Stauffer, S., Brady-Kalnay, S., Hoimes, C., Lee, Z., & Basilion, J. P. (2021). Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer. Cancers, 13(3), 417. https://doi.org/10.3390/cancers13030417