Targeted delivery of cytotoxic proteins to prostate cancer via conjugation to small molecule urea-based PSMA inhibitors
| Autor: | Ronnie C. Mease, Martin G. Pomper, Samuel R. Denmeade, D. M. Rosen, Lizamma Antony, O. C. Rogers, Xiaoping Yang, H. M. Harper, Deepankar Das, Il Minn |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Proteases Science Carboxypeptidases urologic and male genital diseases Article 03 medical and health sciences Prostate cancer 0302 clinical medicine Drug Delivery Systems Cell Line Tumor medicine Pseudomonas exotoxin Cytotoxic T cell Humans Urea Cytotoxicity Cancer Multidisciplinary biology Chemistry Drug discovery Immunotoxins Prostatic Neoplasms Prostate-Specific Antigen medicine.disease In vitro Granzyme B 030104 developmental biology Oncology 030220 oncology & carcinogenesis Cancer research biology.protein Medicine Kallikreins Antibody |
| Zdroj: | Scientific Reports Scientific Reports, Vol 11, Iss 1, Pp 1-13 (2021) |
| ISSN: | 2045-2322 |
| Popis: | Prostate cancer cells are characterized by a remarkably low proliferative rate and the production of high levels of prostate-specific proteases. Protein-based toxins are attractive candidates for prostate cancer therapy because they kill cells via proliferation-independent mechanisms. However, the non-specific cytotoxicity of these potent cytotoxins must be redirected to avoid toxicity to normal tissues. Prostate-Specific Membrane Antigen (PSMA) is membrane-bound carboxypeptidase that is highly expressed by prostate cancer cells. Potent dipeptide PSMA inhibitors have been developed that can selectively deliver and concentrate imaging agents within prostate cancer cells based on continuous PSMA internalization and endosomal cycling. On this basis, we conjugated a PSMA inhibitor to the apoptosis-inducing human protease Granzyme B and the potent Pseudomonas exotoxin protein toxin fragment, PE35. We assessed selective PSMA binding and entrance into tumor cell to induce cell death. We demonstrated these agents selectively bound to PSMA and became internalized. PSMA-targeted PE35 toxin was selectively toxic to PSMA producing cells in vitro. Intratumoral and intravenous administration of this toxin produced marked tumor killing of PSMA-producing xenografts with minimal host toxicity. These studies demonstrate that urea-based PSMA inhibitors represent a simpler, less expensive alternative to antibodies as a means to deliver cytotoxic proteins to prostate cancer cells. |
| Databáze: | OpenAIRE |
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