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Targeted delivery of cytotoxic proteins to prostate cancer via conjugation to small molecule urea-based PSMA inhibitors.

ABSTRACT: 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.

SUBMITTER: Rogers OC

PROVIDER: S-EPMC8295317 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Due to its high and consistent expression in prostate cancer (PCa), the prostate-specific membrane antigen (PSMA) represents an ideal target for molecular imaging and targeted therapy using highly specific radiolabeled PSMA ligands. To address the continuously growing clinical demand for 18F-labeled PSMA-probes, we developed two novel Glu-urea-Glu-(EuE)-based inhibitors, EuE-k-18F-FBOA (1) and EuE-k-?-a-18F-FPyl (2), both with optimized linker structure and different 18F-labeled aromatic moieties. The inhibitors were evaluated in a comparative preclinical study with 18F-DCFPyl and 18F-PSMA-1007. RESULTS:Radiolabeling procedures allowed preparation of (1) and (2) with high radiochemical yields (67?±?7 and 53?±?7%, d.c.) and purity (>?98%). When compared with 18F-DCFPyl (IC50 = 12.3?±?1.2 nM) and 18F-PSMA-1007 (IC50 = 4.2?±?0.5 nM), both metabolically stable EuE-based ligands showed commensurable or higher PSMA affinity (IC50 = 4.2?±?0.4 nM (1), IC50 = 1.1?±?0.2 nM (2)). Moreover, 1.4- and 2.7-fold higher internalization rates were observed for (1) and (2), respectively, resulting in markedly enhanced tumor accumulation in LNCaP-tumor-bearing mice ((1) 12.7?±?2.0% IA/g, (2) 13.0°?±?1.0% IA/g vs. 7.3?±?1.0% IA/g (18F-DCFPyl), 7.1?±?1.5% IA/g (18F-PSMA-1007), 1 h p.i.). In contrast to (1), (2) showed higher kidney accumulation and delayed clearance kinetics. Due to the high hydrophilicity of both compounds, almost no unspecific uptake in non-target tissue was observed. In contrast, due to the less hydrophilic character (logP?=?-?1.6) and high plasma protein binding (98%), 18F-PSMA-1007 showed uptake in non-target tissue and predominantly hepatobiliary excretion, whereas, 18F-DCFPyl exhibited pharmacokinetics quite similar to those obtained with (1) and (2). CONCLUSION:Both 18F-labeled EuE-based PSMA ligands showed excellent in vitro and in vivo PSMA-targeting characteristics. The substantially higher tumor accumulation in mice compared to recently introduced 18F-PSMA-1007 and 18F-DCFPyl suggests their high value for preclinical studies investigating the effects on PSMA-expression. In contrast to (2), (1) seems to be more promising for further investigation, due to the more reliable 18F-labeling procedure, the faster clearance kinetics with comparable high tumor uptake, resulting therefore in better high-contrast microPET imaging as early as 1 h p.i.

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Targeted delivery of cytotoxic proteins to prostate cancer via conjugation to small molecule urea-based PSMA inhibitors.

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