Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer
-
- Xinning Wang
- Department of Biomedical Engineering, Case Western Reserve University, 11100 Euclid Ave, Wearn Building B-49, Cleveland, OH 44106, USA
-
- Aditi Shirke
- Department of Biomedical Engineering, Case Western Reserve University, 11100 Euclid Ave, Wearn Building B-49, Cleveland, OH 44106, USA
-
- Ethan Walker
- Department of Biomedical Engineering, Case Western Reserve University, 11100 Euclid Ave, Wearn Building B-49, Cleveland, OH 44106, USA
-
- Rongcan Sun
- Department of Radiology, Case Western Reserve University, 11100 Euclid Ave, Wearn Building B-44, Cleveland, OH 44106, USA
-
- Gopolakrishnan Ramamurthy
- Department of Radiology, Case Western Reserve University, 11100 Euclid Ave, Wearn Building B-44, Cleveland, OH 44106, USA
-
- Jing Wang
- Department of Radiology, Case Western Reserve University, 11100 Euclid Ave, Wearn Building B-44, Cleveland, OH 44106, USA
-
- Lingpeng Shan
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, 2103 Cornell Rd, Cleveland, OH 44106, USA
-
- Joey Mangadlao
- Department of Radiology, Case Western Reserve University, 11100 Euclid Ave, Wearn Building B-44, Cleveland, OH 44106, USA
-
- Zhipeng Dong
- Department of Mechanical Engineering, Case Western Reserve University, 2190 Adelbert Rd, Cleveland, OH 44106, USA
-
- Jing Li
- Department of Chemistry, Case Western Reserve University, 2080 Adelbert Rd, Cleveland, OH 44106, USA
-
- Ziying Wang
- Department of Mechanical Engineering, Case Western Reserve University, 2190 Adelbert Rd, Cleveland, OH 44106, USA
-
- Mark Schluchter
- Department of Population and Quantitative Health Sciences, Case Western Reserve University, 2103 Cornell Rd, Cleveland, OH 44106, USA
-
- Dong Luo
- Department of Radiology, Case Western Reserve University, 11100 Euclid Ave, Wearn Building B-44, Cleveland, OH 44106, USA
-
- Yu Wang
- Department of Radiology, Case Western Reserve University, 11100 Euclid Ave, Wearn Building B-44, Cleveland, OH 44106, USA
-
- Shaun Stauffer
- Center for Therapeutics Discovery, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA
-
- Susann Brady-Kalnay
- Department of Molecular Biology and Micro Biology, Case Western Reserve University, 2190 Adelbert Rd, Cleveland, OH 44106, USA
-
- Christopher Hoimes
- Duke Cancer Institute, School of Medicine, Duke University, 905 S LaSalle St, GSRB2, Durham, NC 27710, USA
-
- Zhenghong Lee
- Department of Radiology, Case Western Reserve University, 11100 Euclid Ave, Wearn Building B-44, Cleveland, OH 44106, USA
-
- James P. Basilion
- Department of Biomedical Engineering, Case Western Reserve University, 11100 Euclid Ave, Wearn Building B-49, Cleveland, OH 44106, USA
説明
<jats:p>Metastatic castration-resistant prostate cancer poses a serious clinical problem with poor outcomes and remains a deadly disease. New targeted treatment options are urgently needed. PSMA is highly expressed in prostate cancer and has been an attractive biomarker for the treatment of prostate cancer. In this study, we explored the feasibility of targeted delivery of an antimitotic drug, monomethyl auristatin E (MMAE), to tumor tissue using a small-molecule based PSMA lig-and. With the aid of Cy5.5, we found that a cleavable linker is vital for the antitumor activity of the ligand–drug conjugate and have developed a new PSMA-targeting prodrug, PSMA-1-VcMMAE. In in vitro studies, PSMA-1-VcMMAE was 48-fold more potent in killing PSMA-positive PC3pip cells than killing PSMA-negative PC3flu cells. In in vivo studies, PSMA-1-VcMMAE significantly inhibited tumor growth leading to prolonged animal survival in different animal models, including metastatic prostate cancer models. Compared to anti-PSMA antibody-MMAE conjugate (PSMA-ADC) and MMAE, PSMA-1-VcMMAE had over a 10-fold improved maximum tolerated dose, resulting in improved therapeutic index. The small molecule–drug conjugates reported here can be easily synthesized and are more cost efficient than anti-body–drug conjugates. The therapeutic profile of the PSMA-1-VcMMAE encourages further clin-ical development for the treatment of advanced prostate cancer.</jats:p>
収録刊行物
-
- Cancers
-
Cancers 13 (3), 417-, 2021-01-22
MDPI AG