Prostate-specific membrane antigen (PSMA) targeted singlet oxygen delivery via endoperoxide tethered ligands.

Singlet oxygen is the primary agent responsible for the therapeutic effects of photodynamic therapy (PDT). In this work, we demonstrate that singlet oxygen release due to thermal endoperoxide cycloreversion can be targeted towards specific features of selected cancer cells, and this targeted singlet oxygen delivery can serve as an effective therapeutic tool. Thus, cytotoxic singlet oxygen can be delivered regioselectively into prostate specific membrane antigen (PSMA) overexpressing lymph node carcinoma (LNCaP) cells. However, unlike typical photodynamic processes, there is no need for light or oxygen. The potential of the approach is exciting, considering the limitations on the availability of light and oxygen in deep-seated tumors.

Biodistribution and internal radiation dosimetry of a companion diagnostic radiopharmaceutical, [68Ga]PSMA-11, in subcutaneous prostate cancer xenograft model mice.

[68Ga]PSMA-11 is a prostate-specific membrane antigen (PSMA)-targeting radiopharmaceutical for diagnostic PET imaging. Its application can be extended to targeted radionuclide therapy (TRT). In this study, we characterize the biodistribution and pharmacokinetics of [68Ga]PSMA-11 in PSMA-positive and negative (22Rv1 and PC3, respectively) tumor-bearing mice and subsequently estimated its internal radiation dosimetry via voxel-level dosimetry using a dedicated Monte Carlo simulation to evaluate the absorbed dose in the tumor directly. Consequently, this approach overcomes the drawbacks of the conventional organ-level (or phantom-based) method. The kidneys and urinary bladder both showed substantial accumulation of [68Ga]PSMA-11 without exhibiting a washout phase during the study. For the tumor, a peak concentration of 4.5 ± 0.7 %ID/g occurred 90 min after [68Ga]PSMA-11 injection. The voxel- and organ-level methods both determined that the highest absorbed dose occurred in the kidneys (0.209 ± 0.005 Gy/MBq and 0.492 ± 0.059 Gy/MBq, respectively). Using voxel-level dosimetry, the absorbed dose in the tumor was estimated as 0.024 ± 0.003 Gy/MBq. The biodistribution and pharmacokinetics of [68Ga]PSMA-11 in various organs of subcutaneous prostate cancer xenograft model mice were consistent with reported data for prostate cancer patients. Therefore, our data supports the use of voxel-level dosimetry in TRT to deliver personalized dosimetry considering patient-specific heterogeneous tissue compositions and activity distributions.

Darolutamide Potentiates the Antitumor Efficacy of a PSMA-targeted Thorium-227 Conjugate by a Dual Mode of Action in Prostate Cancer Models.

PURPOSE: Androgen receptor (AR) inhibitors are well established in the treatment of castration-resistant prostate cancer and have recently shown efficacy also in castration-sensitive prostate cancer. Although most patients respond well to initial therapy, resistance eventually develops, and thus, more effective therapeutic approaches are needed. Prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer and presents an attractive target for radionuclide therapy. Here, we evaluated the efficacy and explored the mode of action of the PSMA-targeted thorium-227 conjugate (PSMA-TTC) BAY 2315497, an antibody-based targeted alpha-therapy, in combination with the AR inhibitor darolutamide. EXPERIMENTAL DESIGN: The in vitro and in vivo antitumor efficacy and mode of action of the combination treatment were investigated in preclinical cell line-derived and patient-derived prostate cancer xenograft models with different levels of PSMA expression. RESULTS: Darolutamide induced the expression of PSMA in androgen-sensitive VCaP and LNCaP cells in vitro, and the efficacy of darolutamide in combination with PSMA-TTC was synergistic in these cells. In vivo, the combination treatment showed synergistic antitumor efficacy in the low PSMA-expressing VCaP and in the high PSMA-expressing ST1273 prostate cancer models, and enhanced efficacy in the enzalutamide-resistant KUCaP-1 model. The treatments were well tolerated. Mode-of-action studies revealed that darolutamide induced PSMA expression, resulting in higher tumor uptake of PSMA-TTC, and consequently, higher antitumor efficacy, and impaired PSMA-TTC-mediated induction of DNA damage repair genes, potentially contributing to increased DNA damage. CONCLUSIONS: These results provide a strong rationale to investigate PSMA-TTC in combination with AR inhibitors in patients with prostate cancer.

Long-Circulating Prostate-Specific Membrane Antigen-Targeted NIR Phototheranostic Agent.

Targeted photodynamic therapy (PDT) combined with image-guided surgical resection is a promising strategy for precision cancer treatment. Prostate-specific membrane antigen (PSMA) is an attractive target due to its pronounced overexpression in a variety of tumors, most notably in prostate cancer. Recently, we reported a pyropheophorbide-based PSMA-targeted agent, which exhibited long plasma circulation time and effective tumor accumulation. To further advance PSMA-targeted photodynamic therapy by harvesting tissue-penetrating properties of the NIR light, we developed a bacteriochlorophyll-based PSMA-targeted photosensitizer (BPP), consisting of three building blocks: (1) a PSMA-affinity ligand, (2) a peptide linker to prolong plasma circulation time and (3) a bacteriochlorophyll photosensitizer for NIR fluorescence imaging and photodynamic therapy (Qy absorption maximum at 750 nm). BPP exhibited excellent PSMA-targeting selectivity in both subcutaneous and orthotopic mouse models. The nine D-peptide linker in BPP structure prolonged its plasma circulation time (12.65 h). Favorable pharmacokinetic properties combined with excellent targeting selectivity enabled effective BPP tumor accumulation, which led to effective PDT in a subcutaneous prostate adenocarcinoma mouse model. Overall, bright NIR fluorescence of BPP enables effective image guidance for surgical resection, while the combination of its targeting capabilities and PDT activity allows for potent and precise image-guided photodynamic treatment of PSMA-expressing tumors.

A role for N-acetylaspartylglutamate (NAAG) and mGluR3 in cognition.

The peptide transmitter N-acetylaspartylglutamate (NAAG) and its receptor, the type 3 metabotropic glutamate receptor (mGluR3, GRM3), are prevalent and widely distributed in the mammalian nervous system. Drugs that inhibit the inactivation of synaptically released NAAG have procognitive activity in object recognition and other behavioral models. These inhibitors also reverse cognitive deficits in animal models of clinical disorders. Antagonists of mGluR3 block these actions and mice that are null mutant for this receptor are insensitive to the actions of these procognitive drugs. A positive allosteric modulator of this receptor also has procognitive activity. While some data suggest that drugs acting on mGluR3 achieve their procognitive action by increasing arousal during acquisition training, exploration of the procognitive efficacy of NAAG is in its early stages and thus substantial opportunities exist to define the breadth and nature of this activity.

Efficacy Against Human Prostate Cancer by Prostate-specific Membrane Antigen-specific, Transforming Growth Factor-ß Insensitive Genetically Targeted CD8+ T-cells Derived from Patients with Metastatic Castrate-resistant Disease.

Current immunotherapy has limited efficacy on metastatic castrate-resistant prostate cancer (mCRPC). We therefore sought to improve the antitumor ability of mCRPC patient-derived CD8+ T-cells by the endowment of specificity to prostate-specific membrane antigen (PSMA) and insensitivity to immunosuppressant molecule transforming growth factor-ß (TGF-ß) under the control of herpes simplex virus-1 thymidine kinase. CD8+ T-cells were collected by leukapheresis and cultured in a Food and Drug Administration-approved Cell Processing Work Station. We developed a chimeric antigen receptor retroviral construct using an anti-PSMA chimeric immunoglobulin-T-cell receptor(ζ) gene (PZ1) and dominant negative TGF-ß type II receptor (TßRIIDN), that could induce CD8+ T-cells to be PSMA reactive and insensitive to TGF-ß. Cr51 release assay was performed on PC-3 and PC-3-PSMA. The further antitumor functions of PSMA-specific, TGF-ß insensitive CD8+ T-cells was evaluated using an immunodeficient RAG-1-/- mouse model. We found PSMA-specific, TGF-ß insensitive CD8+ T-cells from mCRPC were expanded with strong expression of PZ1 and thymidine kinase genes, and their growth was not suppressed by TGF-ß. The survival of these cells decreased sharply after treatment with ganciclovir. Treatment of PSMA-specific TGF-ß, insensitive CD8+ T-cells was associated with 61.58% specific lysis on PC-3-PSMA, and significantly suppressed PC3-PSMA tumor compared with the PC3 tumor. A large amount of tumor apoptosis and CD8+ T-cell infiltration were found only in the PC3-PSMA tumor. This study verified that PSMA-specific, TGF-ß insensitive CD8+ T-cells derived from mCRPC patients could be successfully expanded and used to overcome the immunosuppressive effects of the tumor microenvironment to control PSMA-expressing PC in vitro and in vivo. This may provide a promising approach for men with mCRPC who fail androgen deprivation therapy. PATIENT SUMMARY: We investigated the role of a novel chimeric antigen receptor T-immunotherapy based on autologous metastatic castrate-resistant prostate cancer patient-derived prostate-specific membrane antigen (PSMA)-specific, transforming growth factor-ß insensitive CD8+ T-cells on PSMA-positive prostate cancer. We found that this chimeric antigen receptor T-cells could kill PSMA-positive prostate cancer specifically. The results suggest that this novel immunotherapy treatment is a potential new approach for men with metastatic castrate-resistant prostate cancer.

Evaluation of Polymeric Nanomedicines Targeted to PSMA: Effect of Ligand on Targeting Efficiency.

Targeted nanomedicines offer a strategy for greatly enhancing accumulation of a therapeutic within a specific tissue in animals. In this study, we report on the comparative targeting efficiency toward prostate-specific membrane antigen (PSMA) of a number of different ligands that are covalently attached by the same chemistry to a polymeric nanocarrier. The targeting ligands included a small molecule (glutamate urea), a peptide ligand, and a monoclonal antibody (J591). A hyperbranched polymer (HBP) was utilized as the nanocarrier and contained a fluorophore for tracking/analysis, whereas the pendant functional chain-ends provided a handle for ligand conjugation. Targeting efficiency of each ligand was assessed in vitro using flow cytometry and confocal microscopy to compare degree of binding and internalization of the HBPs by human prostate cancer (PCa) cell lines with different PSMA expression status (PC3-PIP (PSMA+) and PC3-FLU (PSMA-). The peptide ligand was further investigated in vivo, in which BALB/c nude mice bearing subcutaneous PC3-PIP and PC3-FLU PCa tumors were injected intravenously with the HBP-peptide conjugate and assessed by fluorescence imaging. Enhanced accumulation in the tumor tissue of PC3-PIP compared to PC3-FLU highlighted the applicability of this system as a future imaging and therapeutic delivery vehicle.

Antibody-drug conjugates targeting prostate-specific membrane antigen.

Prostate-specific membrane antigen (PSMA) is an integral, non-shed membrane glycoprotein that is a well-characterized and clinically validated marker of prostate cancer. The expression profile and other biological properties of PSMA make it an attractive target for antibody-drug conjugate (ADC) therapy of prostate cancer, as well as a broad range of other tumors in which PSMA is abundantly expressed within the tumor neovasculature. PSMA-targeted ADCs have been developed using auristatin and maytansinoid drugs, and each ADC has undergone extensive preclinical testing and has completed phase 1 testing in men with advanced prostate cancer. The preclinical and clinical findings have largely substantiated the promise of PSMA as an ADC target. This report summarizes the completed studies, current status, and potential future directions for ADCs that target PSMA.

Targeted therapies for prostate cancer against the prostate specific membrane antigen.

Prostate cancer is the most common cancer in men from Western industrialized countries and a significant proportion of patients progress to advanced metastatic disease, for which currently no curative treatment exists. Therefore, new therapeutic approaches need to be considered. Prostate specific membrane antigen (PSMA) is an integral, non-shed type 2 membrane protein that is highly and specifically expressed on prostate epithelial cells and strongly upregulated in prostate cancer. PSMA is also present in the neovasculature of other solid tumors. These findings have spurred the development of PSMA-targeted therapies and first-generation products have entered clinical testing. The proposed strategies range from targeted toxins and radionuclides to immunotherapeutic agents. The present review provides an overview of these approaches.