RESUMEN
Prostate cancer (PC) is the fifth leading cause of cancer-related deaths among men worldwide. Prostate-specific membrane antigen (PSMA), a molecular target of PC, is clinically used for the treatment and diagnosis of PC using radioligand approaches. However, no PSMA-based chemotherapies have yet been approved by the FDA. Here, we present a novel therapeutic approach using PSMA-targeted 2-deoxyglucose-dendrimer (PSMA-2DG-D) for targeted delivery of a potent tyrosine kinase inhibitor, cabozantinib (Cabo), selectively to PC cells. PSMA-2DG-D demonstrates intracellular localization in PSMA (+) PC cells through PSMA-mediated internalization. This PSMA-specific targeting translates to enhanced efficacy of Cabo compared to the free drug when conjugated to PSMA-2DG-D. Furthermore, systemically administered fluorescently labeled PSMA-2DG-D-Cy5 specifically targets PSMA (+) tumors with minimal off-target accumulation in the PC3-PIP tumor xenograft mouse model. This demonstrates that the PSMA-2DG-D platform is a promising new delivery system for potent chemotherapeutics, where systemic side effects are a significant concern.
Asunto(s)
Antígenos de Superficie , Dendrímeros , Desoxiglucosa , Glutamato Carboxipeptidasa II , Neoplasias de la Próstata , Piridinas , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Animales , Ratones , Desoxiglucosa/farmacología , Desoxiglucosa/química , Piridinas/química , Piridinas/administración & dosificación , Piridinas/farmacología , Glutamato Carboxipeptidasa II/metabolismo , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Dendrímeros/química , Antígenos de Superficie/metabolismo , Anilidas/farmacología , Anilidas/administración & dosificación , Anilidas/farmacocinética , Anilidas/química , Nanomedicina/métodos , Línea Celular Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Desnudos , Sistemas de Liberación de Medicamentos/métodosRESUMEN
Peripheral nerve injuries (PNIs) represent a significant clinical challenge, particularly in elderly populations where axonal remyelination and regeneration are impaired. Developing therapies to enhance these processes is crucial for improving PNI repair outcomes. Glutamate carboxypeptidase II (GCPII) is a neuropeptidase that plays a pivotal role in modulating glutamate signaling through its enzymatic cleavage of the abundant neuropeptide N-acetyl aspartyl glutamate (NAAG) to liberate glutamate. Within the PNS, GCPII is expressed in Schwann cells and activated macrophages, and its expression is amplified with aging. In this study, we explored the therapeutic potential of inhibiting GCPII activity following PNI. We report significant GCPII protein and activity upregulation following PNI, which was normalized by the potent and selective GCPII inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA). In vitro, 2-PMPA robustly enhanced myelination in dorsal root ganglion (DRG) explants. In vivo, using a sciatic nerve crush injury model in aged mice, 2-PMPA accelerated remyelination, as evidenced by increased myelin sheath thickness and higher numbers of remyelinated axons. These findings suggest that GCPII inhibition may be a promising therapeutic strategy to enhance remyelination and potentially improve functional recovery after PNI, which is especially relevant in elderly PNI patients where this process is compromised.
Asunto(s)
Glutamato Carboxipeptidasa II , Traumatismos de los Nervios Periféricos , Remielinización , Animales , Ratones , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Traumatismos de los Nervios Periféricos/metabolismo , Remielinización/efectos de los fármacos , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Glutamato Carboxipeptidasa II/metabolismo , Vaina de Mielina/metabolismo , Vaina de Mielina/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ratones Endogámicos C57BL , Regeneración Nerviosa/efectos de los fármacos , Nervio Ciático/lesiones , Nervio Ciático/efectos de los fármacos , Masculino , Axones/efectos de los fármacos , Axones/metabolismoRESUMEN
BACKGROUND: Both apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) inhibition and melatonin suppress prostate cancer (PCa) growth. OBJECTIVE: This study evaluated the therapeutic efficiency of self-assembled and prostate-specific membrane antigen (PSMA)-targeted nanocarrier loading 125I radioactive particles and encapsulating siRNA targeting APE1 (siAPE1) and melatonin for PCa. METHODS: The linear polyarginine R12 polypeptide was prepared using Fmoc-Arg-Pbf-OH. The PSMA-targeted polymer was synthesized by conjugating azide-modified R12 peptide to PSMA monoclonal antibody (mAb). Before experiments, the PSMA-R12 nanocarrier was installed with melatonin and siAPE1, which were subsequently labeled by 125I radioactive particles. In vitro biocompatibility and cytotoxicity of nanocomposites were examined in LNCaP cells and in vivo biodistribution and pharmacokinetics were determined using PCa tumor-bearing mice. RESULTS: PSMA-R12 nanocarrier was ~120 nm in size and was increased to ~150 nm by melatonin encapsulation. PSMA-R12 nanoparticles had efficient loading capacities of siAPE1, melatonin, and 125I particles. The co-delivery of melatonin and siAPE1 by PSMA-R12-125I showed synergistic effects on suppressing LNCaP cell proliferation and Bcl-2 expression and promoting cell apoptosis and caspase-3 expression. Pharmacokinetics analysis showed that Mel@PSMA-R12-125I particles had high uptake activity in the liver, spleen, kidney, intestine, and tumor, and were accumulated in the tumor sites within the first 8 h p.i., but was rapidly cleared from all the tested organs at 24 h p.i. Administration of nanoparticles to PCa tumors in vivo showed that Mel@PSMA-R12- 125I/siAPE1 had high efficiency in suppressing PCa tumor growth. CONCLUSION: The PSMA-targeted nanocarrier encapsulating siAPE1 and melatonin is a promising therapeutic strategy for PCa and can provide a theoretical basis for patent applications.
Asunto(s)
Antígenos de Superficie , Glutamato Carboxipeptidasa II , Radioisótopos de Yodo , Melatonina , Nanopartículas , Neoplasias de la Próstata , Masculino , Animales , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Humanos , Radioisótopos de Yodo/administración & dosificación , Melatonina/farmacología , Melatonina/administración & dosificación , Línea Celular Tumoral , Nanopartículas/química , Ratones , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Glutamato Carboxipeptidasa II/metabolismo , Distribución Tisular , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Apoptosis/efectos de los fármacos , Ratones Endogámicos BALB C , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/farmacologíaRESUMEN
In this study, we have developedsmall molecule drug conjugates (SMDCs)consisting ofa prostate specific membrane antigen (PSMA) ligandand syringolin derivatives, which are potent proteasome inhibitors, to selectively deliver syringolin derivatives to prostate cancer cells. Two parent compounds were used for syringolin derivatives with different linkage sites. These SMDCs exhibited PSMA-expressing cell-selective cytotoxicity and they could potentially be used for safer treatment of cancer.
Asunto(s)
Antígenos de Superficie , Antineoplásicos , Glutamato Carboxipeptidasa II , Inhibidores de Proteasoma , Humanos , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/química , Inhibidores de Proteasoma/síntesis química , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Glutamato Carboxipeptidasa II/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Antígenos de Superficie/metabolismo , Relación Estructura-Actividad , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/síntesis química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismoRESUMEN
Prostate-specific membrane antigen (PSMA) overexpressed in prostate cancer cells can serve as a target for imaging and radioligand therapy (RLT). Previously, [68Ga]Ga-P16-093, containing a Ga(III) chelator, N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N'-diacetic acid (HBED-CC), displayed excellent PSMA-targeting properties and showed a high tumor uptake and retention useful for diagnosis in prostate cancer patients. Recently, [177Lu]Lu-PSMA-617 has been approved by the U.S. food and drug administration (FDA) for the treatment of prostate cancer patients. Derivatives of PSMA-093 using AAZTA (6-amino-6-methylperhydro-1,4-diazepinetetraacetic acid), as the chelator, were designed as alternative agents forming complexes with both diagnostic and therapeutic radiometals, such as gallium-68 (log K = 22.18) or lutetium-177 (log K = 21.85). The aim of this study is to evaluate AAZTA-Gly-O-(methylcarboxy)-Tyr-Phe-Lys-NH-CO-NH-Glu (designated as AZ-093, 1) leading to a gallium-68/lutetium-177 theranostic pair as potential PSMA targeting agents. Synthesis of the desired precursor, AZ-093, 1, was effectively accomplished. Labeling with either [68Ga]GaCl3 or [177Lu]LuCl3 in a sodium acetate buffer solution (pH 4-5) at 50 °C in 5 to 15 min produced either [68Ga]Ga-1 or [177Lu]Lu-1 with high yields and excellent radiochemical purities. Results of in vitro binding studies, cell uptake, and retention (using PSMA-positive prostate carcinoma cells line, 22Rv1-FOLH1-oe) were comparable to that of [68Ga]Ga-P16-093 and [177Lu]Lu-PSMA-617, respectively. Specific cellular uptake was determined with or without the competitive blocking agent (2 µM of "cold" PSMA-11). Cellular binding and internalization showed a time-dependent increase over 2 h at 37 °C in the PSMA-positive cells. The cell uptakes were completely blocked by the "cold" PSMA-11 suggesting that they are competing for the same PSMA binding sites. In the mouse model with implanted PSMA-positive tumor cells, both [68Ga]Ga-1 and [177Lu]Lu-1 displayed excellent uptake and retention in the tumor. Results indicate that [68Ga]Ga/[177Lu]Lu-1 (68Ga]Ga/[177Lu]Lu-AZ-093) is potentially useful as PSMA-targeting agent for both diagnosis and radiotherapy of prostate cancer.
Asunto(s)
Antígenos de Superficie , Radioisótopos de Galio , Glutamato Carboxipeptidasa II , Lutecio , Neoplasias de la Próstata , Radiofármacos , Masculino , Humanos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/radioterapia , Neoplasias de la Próstata/metabolismo , Lutecio/química , Antígenos de Superficie/metabolismo , Radiofármacos/química , Radiofármacos/farmacología , Radiofármacos/farmacocinética , Glutamato Carboxipeptidasa II/metabolismo , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Línea Celular Tumoral , Radioisótopos/química , Animales , Quelantes/química , Antígeno Prostático Específico/metabolismo , Distribución Tisular , Ratones , Ácido Edético/análogos & derivados , Ácido Edético/química , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodosRESUMEN
Prostate cancer (PCa) is one of the most common tumors in men, with the overexpression of prostate-specific membrane. In this study, we developed four new 68Ga-labeled PSMA-targeting tracers by introducing quinoline, phenylalanine and decanoic acid groups to enhance their lipophilicity, strategically limiting their metabolic pathway through the urinary system. Four radiotracers were synthesized with radiochemical purity >95 %, and exhibited high stability in vivo and in vitro. The inhibition constants (Ki) of SDTWS01-04 to PSMA were in the nanomolar range (<10 nM). Micro PET/CT imaging and biodistribution analysis revealed that 68Ga-SDTWS01 enabled clear tumor visualization in PET images at 1.5 h post-injection, with excellent pharmacokinetic properties. Notably, the kidney uptake of 68Ga-SDTWS01 significantly reduced, with higher tumor-to-kidney ratio (0.36 ± 0.02), tumor-to-muscle ratio (24.31 ± 2.10), compared with 68Ga-PSMA-11 (T/K: 0.15 ± 0.01; T/M: 14.97 ± 1.40), suggesting that 68Ga-SDTWS01 is a promising radiotracer for the diagnosis of PCa. Moreover, SDTWS01 with a chelator DOTA could also label 177Lu and 225Ac, which could be used for the treatment of PCa.
Asunto(s)
Radioisótopos de Galio , Glutamato Carboxipeptidasa II , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Radioisótopos de Galio/química , Humanos , Masculino , Animales , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Glutamato Carboxipeptidasa II/metabolismo , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Distribución Tisular , Ratones , Radiofármacos/síntesis química , Radiofármacos/química , Radiofármacos/farmacología , Antígenos de Superficie/metabolismo , Estructura Molecular , Línea Celular TumoralRESUMEN
ABSTRACT: Prostate cancer (PCa) is the most common noncutaneous malignancy in men. Until recent years, accurate imaging of men with newly diagnosed PCa, or recurrent or low-volume metastatic disease, was limited. Further, therapeutic options for men with advanced, metastatic, castration-resistant disease were increasingly limited as a result of increasing numbers of systemic therapies being combined in the upfront metastatic setting. The advent of urea-based, small-molecule inhibitors of prostate-specific membrane antigen (PSMA) has partially addressed those shortcomings in diagnosis and therapy of PCa. On the diagnostic side, there are multiple pivotal phase III trials with several different agents having demonstrated utility in the initial staging setting, with generally modest sensitivity but very high specificity for determining otherwise-occult pelvic nodal involvement. That latter statistic drives the utility of the scan by allowing imaging interpreters to read with very high sensitivity while maintaining a robust specificity. Other pivotal phase III trials have demonstrated high detection efficiency in patients with biochemical failure, with high positive predictive value at the lesion level, opening up possible new avenues of therapy such as metastasis-directed therapy. Beyond the diagnostic aspects of PSMA-targeted radiotracers, the same urea-based chemical scaffolds can be altered to deliver therapeutic isotopes to PCa cells that express PSMA. To date, one such agent, when combined with best standard-of-care therapy, has demonstrated an ability to improve overall survival, progression-free survival, and freedom from skeletal events relative to best standard-of-care therapy alone in men with metastatic, castration-resistant PCa who are post chemotherapy. Within the current milieu, there are a number of important future directions including the use of artificial intelligence to better leverage diagnostic findings, further medicinal chemistry refinements to the urea-based structure that may allow improved tumor targeting and decreased toxicities, and the incorporation of new radionuclides that may better balance efficacy with toxicities than those nuclides that are available.
Asunto(s)
Antígenos de Superficie , Glutamato Carboxipeptidasa II , Neoplasias de la Próstata , Radiofármacos , Humanos , Masculino , Radiofármacos/administración & dosificación , Radiofármacos/uso terapéutico , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/terapia , Glutamato Carboxipeptidasa II/metabolismo , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Antígenos de Superficie/metabolismoRESUMEN
Clinical trials of prostate-specific membrane antigen (PSMA) targeted radiopharmaceuticals have shown encouraging results. Some agents, like lutetium-177 [177Lu]Lu-PSMA-617 ([177Lu]Lu-PSMA-617), are already approved for late line treatment of metastatic castration-resistant prostate cancer (mCRPC). Projections are for continued growth of this treatment modality; [177Lu]Lu-PSMA-617 is being studied both in earlier stages of disease and in combination with other anti-cancer therapies. Further, the drug development pipeline is deep with variations of PSMA-targeting radionuclides, including higher energy alpha particles conjugated to PSMA-honing vectors. It is safe to assume that an increasing number of patients will be exposed to PSMA-targeted radiopharmaceuticals during the course of their cancer treatment. In this setting, it is important to better understand and mitigate the most commonly encountered toxicities. One particularly vexing side effect is xerostomia. In this review, we discuss the scope of the problem, inventories to better characterize and monitor this troublesome side effect, and approaches to preserve salivary function and effectively palliate symptoms. This article aims to serve as a useful reference for prescribers of PSMA-targeted radiopharmaceuticals, while also commenting on areas of missing data and opportunities for future research.
Asunto(s)
Antígenos de Superficie , Glutamato Carboxipeptidasa II , Radiofármacos , Humanos , Radiofármacos/uso terapéutico , Masculino , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Lutecio/uso terapéutico , Radioisótopos/efectos adversos , Radioisótopos/administración & dosificación , Glándulas Salivales/efectos de la radiación , Glándulas Salivales/efectos de los fármacos , Dipéptidos/uso terapéutico , Compuestos Heterocíclicos con 1 Anillo/uso terapéuticoRESUMEN
INTRODUCTION: Single domain antibody fragments (sdAbs) are an appealing scaffold for radiopharmaceutical development due to their small size (~15 kDa), high solubility, high stability, and excellent tumor penetration. Previously, we developed NB7 sdAb, which has very high affinity for an epitope on PSMA that is different from those targeted by small molecule PSMA inhibitors. Herein, we evaluated NB7 after radioiodination using [*I]SGMIB (1,3,4-isomer) and iso-[*I]SGMIB (1,3,5-isomer), as well as their 211At-labeled analogues. METHODS: [*I]SGMIB, iso-[*I]SGMIB, [211At]SAGMB, and iso-[211At]SAGMB conjugates of NB7 sdAb were synthesized and their binding affinity, cell uptake and internalization were assessed in PSMA+ PC3 PIP and PSMA- PC3 flu cells. Biodistribution studies were performed in mice bearing PSMA+ PC3 PIP xenografts. First, a single-label experiment evaluated the tissue distribution of a NB7 bearing a His6-tag (NB7H6) and labeled with iso-[125I]SGMIB. Three paired-label experiments then were performed to compare: a) NB7 labeled using [*I]SGMIB and iso-[*I]SGMIB, b) 131I- vs 211At-labeled NB7 conjugates and c) [125I]SGMIB-NB7H6 to the small molecule PSMA inhibitor [131I]YF2. RESULTS: All NB7 radioconjugates bound specifically to PSMA with dissociation constants, Kd, in the low nM range (1.4-6.4 nM). An initial biodistribution study demonstrated good tumor uptake for iso-[125I]SGMIB-NB7H6 (7.2 ± 1.5 % ID/g at 1 h) and no deleterious effect of the His6-tag on renal activity levels, which declined to 3.1 ± 1.1 % ID/g by 4 h. Paired-label biodistribution found no distinction between the two SGMIB isomer NB7 conjugates with the [131I]SGMIB-NB7-to-iso-[125I]SGMIB-NB7 tumor uptake ratios not significantly different from unity: 1.06 ± 0.08 at 1 h, 1.04 ± 0.12 at 4 h, and 1.07 ± 0.09 at 24 h. Both isomer conjugates cleared rapidly from normal tissues and exhibited very low uptake in thyroid, lacrimal and salivary glands. Paired-label biodistribution of [131I]SGMIB-NB7H6 and [211At]SAGMB-NB7H6 demonstrated similar tumor uptake and kidney clearance for the two radioconjugates. However, levels of 211At in thyroid, stomach, salivary and lacrimal glands were significantly higher (P < 0.05) that those for 131I suggesting greater dehalogenation for [211At]SAGMB-NB7H6. Finally, co-administration of [125I]SGMIB-NB7H6 and [131I]YF2 demonstrated good tumor uptake for both with considerably more rapid renal clearance for the NB7 radioconjugate. CONCLUSION: NB7 radioconjugates exhibited good accumulation in PSMA-positive xenografts with rapid clearance from kidney and other normal tissues. We conclude that NB7 is a potentially useful scaffold for developing PSMA-targeted theranostics with different characteristics than current small molecule and antibody-based approaches.
Asunto(s)
Antígenos de Superficie , Glutamato Carboxipeptidasa II , Neoplasias de la Próstata , Anticuerpos de Dominio Único , Masculino , Humanos , Animales , Ratones , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Glutamato Carboxipeptidasa II/inmunología , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Glutamato Carboxipeptidasa II/metabolismo , Anticuerpos de Dominio Único/química , Anticuerpos de Dominio Único/inmunología , Antígenos de Superficie/metabolismo , Antígenos de Superficie/inmunología , Línea Celular Tumoral , Distribución Tisular , Transformación Celular NeoplásicaRESUMEN
There is increasing demand worldwide to develop diagnostic and therapeutic (theranostic) markers for prostate cancer. One target of interest is prostate-specific membrane antigen (PSMA), a protein which is overexpressed in prostate cancer cells. Over the past decade, a growing body of literature has demonstrated that radiolabeled ligands that target PSMA show favorable clinical response and survival outcomes in patients with advanced prostate cancer. This focused review provides background to the development of PSMA as a target, an overview of key studies informing our current approach to radioligand-based imaging and therapy for prostate cancer, and a model for real-world implementation of PSMA theranostics based on an Australian experience.
Asunto(s)
Antígenos de Superficie , Biomarcadores de Tumor , Glutamato Carboxipeptidasa II , Medicina de Precisión , Neoplasias de la Próstata , Humanos , Masculino , Australia , Biomarcadores de Tumor/antagonistas & inhibidores , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Medicina de Precisión/métodos , Próstata , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/tratamiento farmacológicoRESUMEN
PURPOSE: Initially, prostate cancer responds to hormone therapy, but eventually resistance develops. Beta emitter-based prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy is approved for the treatment of metastatic castration-resistant prostate cancer. Here we introduce a targeted alpha therapy (TAT) consisting of the PSMA antibody pelgifatamab covalently linked to a macropa chelator and labeled with actinium-225 and compare its efficacy and tolerability with other TATs. EXPERIMENTAL DESIGN: The in vitro characteristics and in vivo biodistribution, antitumor efficacy, and tolerability of 225Ac-macropa-pelgifatamab (225Ac-pelgi) and other TATs were investigated in cell line- and patient-derived prostate cancer xenograft models. The antitumor efficacy of 225Ac-pelgi was also investigated in combination with the androgen receptor inhibitor darolutamide. RESULTS: Actinium-225-labeling of 225Ac-pelgi was efficient already at room temperature. Potent in vitro cytotoxicity was seen in PSMA-expressing (LNCaP, MDA-PCa-2b, and C4-2) but not in PSMA-negative (PC-3 and DU-145) cell lines. High tumor accumulation was seen for both 225Ac-pelgi and 225Ac-DOTA-pelgi in the MDA-PCa-2b xenograft model. In the C4-2 xenograft model, 225Ac-pelgi showed enhanced antitumor efficacy with a T/Cvolume (treatment/control) ratio of 0.10 compared with 225Ac-DOTA-pelgi, 225Ac-DOTA-J591, and 227Th-HOPO-pelgifatamab (227Th-pelgi; all at 300 kBq/kg) with T/Cvolume ratios of 0.37, 0.39, and 0.33, respectively. 225Ac-pelgi was less myelosuppressive than 227Th-pelgi. 225Ac-pelgi showed dose-dependent treatment efficacy in the patient-derived KuCaP-1 model and strong combination potential with darolutamide in both cell line- (22Rv1) and patient-derived (ST1273) xenograft models. CONCLUSIONS: These results provide a strong rationale to investigate 225Ac-pelgi in patients with prostate cancer. A clinical phase I study has been initiated (NCT06052306).
Asunto(s)
Actinio , Partículas alfa , Antígenos de Superficie , Glutamato Carboxipeptidasa II , Ensayos Antitumor por Modelo de Xenoinjerto , Masculino , Humanos , Animales , Ratones , Línea Celular Tumoral , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Glutamato Carboxipeptidasa II/metabolismo , Antígenos de Superficie/metabolismo , Partículas alfa/uso terapéutico , Distribución Tisular , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Radiofármacos/administración & dosificaciónRESUMEN
INTRODUCTION: Whilst prostate cancer is the fourth most common cancer globally, effective therapies for patients with advanced disease are lacking. In recent years, interest in using theranostic agents to treat castrate-resistant prostate cancer (CRPC) and metastatic prostate cancer has emerged. Lu-TLX591 monoclonal antibody is a potential agent of significance; however, to date, reports on its toxicity and efficacy have been limited to small clinical trials in heavily pretreated patients. This retrospective study describes the real-world toxicity and efficacy profile of Lu-TLX591. METHODS: Eighteen patients received Lu-TLX591 at two private oncology centres in Australia. Patients were eligible if they had CRPC or metastatic prostate cancer and prostate-specific membrane antigen (PSMA)-avid disease confirmed by PSMA-positron emission tomography (PET). Patients received two cycles of Lu-TLX591 monoclonal antibody (177 Lu-DOTA-rosopatamab) each dosed from 1.01-2.85 GBq, 14 days apart. Patient side effects, blood test results and radiology reports were recorded on the patient's electronic medical record (eMR). RESULTS: Prominent side effects included fatigue (55.6%), anorexia (16.7%), nausea (11.1%), and transfusion reactions (11.1%). All-grade haematological toxicities included lymphopenia (61.1%), anaemia (22.2%), leukopenia (27.8%), neutropenia (27.8%), and thrombocytopenia (27.8%). Grade 4 toxicity included lymphopenia (6.7%) and thrombocytopenia (6.7%). Patients' prostate-specific antigen (PSA) responses were as follows; ≥ 30% PSA decline (27.8%), ≥ 50% PSA decline (11.4%) and any PSA decline (38.9%). Follow-up radiology revealed 54.5% stable disease, 45.4% disease progression and 9.1% disease regression. CONCLUSION: Lu-TLX591 was safely administered at acceptable toxicity and its efficacy reflects previous clinical trials. Larger studies are required and are underway (NCT04786847; NCT05146973; NCT04876651) to determine Lu-TLX591 effectiveness amongst different prostate cancer populations and compare its efficacy against peptide-based radiopharmaceutical agents.
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Anticuerpos Monoclonales , Lutecio , Radioisótopos , Humanos , Masculino , Anciano , Lutecio/uso terapéutico , Lutecio/efectos adversos , Persona de Mediana Edad , Radioisótopos/efectos adversos , Radioisótopos/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Estudios Retrospectivos , Glutamato Carboxipeptidasa II/inmunología , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Resultado del Tratamiento , Anciano de 80 o más Años , Metástasis de la Neoplasia , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Antígenos de Superficie/inmunología , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Radiofármacos/efectos adversos , Radiofármacos/uso terapéutico , Antígeno Prostático Específico/sangreRESUMEN
BACKGROUND: Despite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer. METHODS: This is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS). DISCUSSION: Our prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT06059014.
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Antígenos de Superficie , Carcinoma de Células Renales , Glutamato Carboxipeptidasa II , Neoplasias Renales , Lutecio , Radioisótopos , Radiofármacos , Humanos , Masculino , Carcinoma de Células Renales/radioterapia , Carcinoma de Células Renales/tratamiento farmacológico , Dipéptidos/efectos adversos , Dipéptidos/uso terapéutico , Compuestos Heterocíclicos con 1 Anillo/efectos adversos , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Lutecio/efectos adversos , Lutecio/uso terapéutico , Estudios Prospectivos , Calidad de Vida , Radioisótopos/efectos adversos , Radioisótopos/uso terapéutico , Resultado del Tratamiento , Microambiente Tumoral , Femenino , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/radioterapia , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Estudios Multicéntricos como Asunto , Antígenos de Superficie/metabolismo , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Radiofármacos/efectos adversos , Radiofármacos/uso terapéuticoRESUMEN
Background: The Glu-Urea-Lys (EUK) pharmacophore as prostate-specific membrane antigen (PSMA)-targeted ligand was synthesized, radiolabeled with 99mTc-tricarbonyl-imidazole-BPS chelation system, and biological activities were evaluated. The strategy [2 + 1] ligand is applied for tricarbonyl labeling. (5-imidazole-1-yl)pentanoic acid as a monodentate ligand and bathophenanthroline disulfonate (BPS) as a bidentate ligand formed a chelate system with 99mTc-tricarbonyl. EUK-pentanoic acid-imidazole and EUK were evaluated for PSMA active site using AutoDock 4 software. Materials and Methods: EUK-pentanoic acid-imidazole was synthesized in two steps. BPS was radiolabeled with 99mTc-tricarbonyl at 100°C for 30 min. The purified 99mTc(CO)3(H2O)BPS was used to radiolabel EUK-pentanoic acid-imidazole at 100°C, 30 min. Radiochemical purity, Log P, and stability studies were carried out within 24 h. Affinity of 99mTc(CO)3BPS-imidazole-EUK was performed in the saturation binding studies using LNCaP cells at 37°C for 1 h with a range of 0.001-1000 nM radiolabeled compound range. Internalization studies were performed in LNCaP cells with 1000 nM radiolabeled compound incubated for (0-2) h at 37°C. Biodistribution was studied in normal male Balb/c mice. The artificial intelligence predicts the uptake of radiolabeled compound in tumor. Results: The structures of synthesized compounds were confirmed by mass spectroscopy. Radiochemical purity, Log P, and protein binding were ≥95%, -0.2%, and 23%, respectively. The radiolabeled compound was stable in saline and human plasma within 24 h with radiochemical purity ≥90%. There was no release of 99mTc within 4 h in competition with histidine. The affinity was 82 ± 26.38 nM, and the activity increased inside the cells over time. Biodistribution studies showed radioactivity accumulation in kidneys less than 99mTc-HYNIC-PSMA. There was a moderate accumulation of radioactivity in the liver and intestine. Conclusion: Based on the results, 99mTc(CO)3BPS-imidazole-EUK can potentially be used as an imaging agent for studies at prostate bed and distal areas. The chelate system can be potentially labeled with rhenium for imaging studies (fluorescent or scintigraphy) and therapy.
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Antígenos de Superficie , Glutamato Carboxipeptidasa II , Animales , Humanos , Masculino , Ratones , Inteligencia Artificial , Quelantes/química , Imidazoles , Ligandos , Próstata , Radiofármacos , Tecnecio/química , Distribución Tisular , Urea/química , Urea/farmacología , Glutamato Carboxipeptidasa II/antagonistas & inhibidoresRESUMEN
There is an urgent need to develop therapeutics for inflammatory bowel disease (IBD) because up to 40% of patients with moderate-to-severe IBD are not adequately controlled with existing drugs. Glutamate carboxypeptidase II (GCPII) has emerged as a promising therapeutic target. This enzyme is minimally expressed in normal ileum and colon, but it is markedly up-regulated in biopsies from patients with IBD and preclinical colitis models. Here, we generated a class of GCPII inhibitors designed to be gut-restricted for oral administration, and we interrogated efficacy and mechanism using in vitro and in vivo models. The lead inhibitor, (S)-IBD3540, was potent (half maximal inhibitory concentration = 4 nanomolar), selective, gut-restricted (AUCcolon/plasma > 50 in mice with colitis), and efficacious in acute and chronic rodent colitis models. In dextran sulfate sodium-induced colitis, oral (S)-IBD3540 inhibited >75% of colon GCPII activity, dose-dependently improved gross and histologic disease, and markedly attenuated monocytic inflammation. In spontaneous colitis in interleukin-10 (IL-10) knockout mice, once-daily oral (S)-IBD3540 initiated after disease onset improved disease, normalized colon histology, and attenuated inflammation as evidenced by reduced fecal lipocalin 2 and colon pro-inflammatory cytokines/chemokines, including tumor necrosis factor-α and IL-17. Using primary human colon epithelial air-liquid interface monolayers to interrogate the mechanism, we further found that (S)-IBD3540 protected against submersion-induced oxidative stress injury by decreasing barrier permeability, normalizing tight junction protein expression, and reducing procaspase-3 activation. Together, this work demonstrated that local inhibition of dysregulated gastrointestinal GCPII using the gut-restricted, orally active, small-molecule (S)-IBD3540 is a promising approach for IBD treatment.
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Colitis , Glutamato Carboxipeptidasa II , Enfermedades Inflamatorias del Intestino , Animales , Humanos , Ratones , Colitis/tratamiento farmacológico , Colitis/metabolismo , Colon/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Inflamación/patología , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/patología , Ratones Endogámicos C57BLRESUMEN
In the past two decades, extensive efforts have been made to develop agents targeting prostate-specific membrane antigen (PSMA) for prostate cancer imaging and therapy. To date, represented by two recent approvals of [68Ga]Ga-PSMA-11 and [18F]F-DCFPyL by the United States Food and Drug Administration (US-FDA) for positron emission tomography (PET) imaging to identify suspected metastases or recurrence in patients with prostate cancer, PSMA-targeting imaging and theranostic agents derived from small molecule PSMA inhibitors have advanced to clinical practice and trials of prostate cancer. The focus of current development of new PSMA-targeting agents has thus shifted to the improvement of in vivo pharmacokinetics and higher specific binding affinity with the aims to further increase the detection sensitivity and specificity and minimize the toxicity to non-target tissues, particularly the kidneys. The main strategies involve systematic chemical modifications of the linkage between the targeting moiety and imaging/therapy payloads. In addition to a summary of the development history of PSMA-targeting agents, this review provides an overview of current advances and future promise of PSMA-targeted imaging and theranostics with focuses on the structural determinants of the chemical modification towards the next generation of PSMA-targeting agents.
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Antígenos de Superficie/metabolismo , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Glutamato Carboxipeptidasa II/metabolismo , Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/radioterapia , Radiofármacos/uso terapéutico , Humanos , Masculino , Medicina de Precisión , Neoplasias de la Próstata/patología , Radiofármacos/metabolismoRESUMEN
PURPOSE: Lutetium labelled prostate-specific membrane antigen radioligand therapy (Lu-PSMA RLT) has shown pleasing early results in management of high-volume metastatic castration resistant prostate cancer (mCRPC), but its role in the early treatment of men with only lymph node metastasis (LNM) is unknown. The aim was to assess the outcome of Lu-PSMA RLT earlier in the treatment of men with only LNM. MATERIALS AND METHODS: Single institution retrospective review of men with only LNM on staging Ga-PSMA PET PSMA who proceeded with Lu-PSMA RLT. RESULTS: There were 17 men with only LNM, including 13 with mCRPC and 3 who were both hormone and chemotherapy naïve. The median PSA was 3.7 (0.46-120 ng/mL). A PSA decline of ≥50% occurred in 10/17 (58.8%), decreasing to <0.2 ng/mL in 35.3% (6/17). The PSA continues to decline or remain stable in 10/17 (58.8%) with a median follow-up of 13 months, and 8/17 (47.1%) have not reached their pre-treatment levels. There were no significant side effects. There was a better PSA response in men without prior chemotherapy (p=0.05). The prostate cancer specific and overall survival is 82.4% (14/17). CONCLUSIONS: Our results identify improved PSA response to Lu-PSMA RLT in men with only LNM, especially in the chemotherapy naïve cohort, compared to previous series with more advanced mCRPC. These findings provide important proof of principle to aid with planning of future prospective randomized trials evaluating the role of Lu-PSMA RLT earlier in the management of node metastatic prostate cancer, including men naïve of ADT and chemotherapy.
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Dipéptidos , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Compuestos Heterocíclicos con 1 Anillo , Lutecio/uso terapéutico , Metástasis Linfática , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración , Antígenos de Superficie , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Dipéptidos/administración & dosificación , Dipéptidos/efectos adversos , Compuestos Heterocíclicos con 1 Anillo/administración & dosificación , Compuestos Heterocíclicos con 1 Anillo/efectos adversos , Humanos , Ligandos , Metástasis Linfática/patología , Metástasis Linfática/terapia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Próstata/patología , Antígeno Prostático Específico/administración & dosificación , Antígeno Prostático Específico/efectos adversos , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/terapia , Radiofármacos/uso terapéutico , Análisis de Supervivencia , Tiempo de Tratamiento , Resultado del Tratamiento , Carga TumoralRESUMEN
(1) Background: Prostate-specific membrane antigen (PSMA) has been extensively studied in the last decade. It became a promising biological target in the diagnosis and therapy of PSMA-expressing cancer diseases. Although there are several radiolabeled PSMA inhibitors available, the search for new compounds with improved pharmacokinetic properties and simplified synthesis is still ongoing. In this study, we developed PSMA ligands with two different hybrid chelators and a modified linker. Both compounds have displayed a promising pharmacokinetic profile. (2) Methods: DATA5m.SA.KuE and AAZTA5.SA.KuE were synthesized. DATA5m.SA.KuE was labeled with gallium-68 and radiochemical yields of various amounts of precursor at different temperatures were determined. Complex stability in phosphate-buffered saline (PBS) and human serum (HS) was examined at 37 °C. Binding affinity and internalization ratio were determined in in vitro assays using PSMA-positive LNCaP cells. Tumor accumulation and biodistribution were evaluated in vivo and ex vivo using an LNCaP Balb/c nude mouse model. All experiments were conducted with PSMA-11 as reference. (3) Results: DATA5m.SA.KuE was synthesized successfully. AAZTA5.SA.KuE was synthesized and labeled according to the literature. Radiolabeling of DATA5m.SA.KuE with gallium-68 was performed in ammonium acetate buffer (1 M, pH 5.5). High radiochemical yields (>98%) were obtained with 5 nmol at 70 °C, 15 nmol at 50 °C, and 60 nmol (50 µg) at room temperature. [68Ga]Ga-DATA5m.SA.KuE was stable in human serum as well as in PBS after 120 min. PSMA binding affinities of AAZTA5.SA.KuE and DATA5m.SA.KuE were in the nanomolar range. PSMA-specific internalization ratio was comparable to PSMA-11. In vivo and ex vivo studies of [177Lu]Lu-AAZTA5.SA.KuE, [44Sc]Sc-AAZTA5.SA.KuE and [68Ga]Ga-DATA5m.SA.KuE displayed specific accumulation in the tumor along with fast clearance and reduced off-target uptake. (4) Conclusions: Both KuE-conjugates showed promising properties especially in vivo allowing for translational theranostic use.
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Antígenos de Superficie/química , Quelantes/química , Glutamato Carboxipeptidasa II/química , Radiofármacos/química , Animales , Quelantes/síntesis química , Técnicas de Química Sintética , Diagnóstico por Imagen/métodos , Modelos Animales de Enfermedad , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Xenoinjertos , Humanos , Marcaje Isotópico , Cinética , Ratones , Estructura Molecular , Neoplasias/diagnóstico por imagen , Neoplasias/etiología , Unión Proteica , Radiofármacos/síntesis química , Investigación Biomédica TraslacionalRESUMEN
68Ga-radiolabeled small molecules that specifically target prostate-specific membrane antigen (PSMA) have been extensively investigated, and some of these tracers have been used in the diagnosis of prostate cancer via 68Ga-positron emission tomography (68Ga-PET). Nevertheless, current 68Ga-labeled radiotracers show only fair detection rates for metastatic prostate cancer lesions, especially those with lower levels of prostate specific antigen (PSA), which often occurs in the biochemical recurrence of prostate cancer. The goal of this study was to design and synthesize a new PSMA-targeted radiotracer, 68Ga-SC691, with high affinity for prostate cancer cells and excellent pharmacokinetics. To this end, structural optimization was carried out on the bifunctional group, target motif, and linker while the high affinity targeting scaffold remained. To explore its potential in the clinic, a comparative study was further performed in vitro and in vivo between 68Ga-SC691 and 68Ga-PSMA-11, a clinically approved tracer for PSMA-positive prostate cancer. SC691 was radiolabeled to provide 68Ga-SC691 in 99% radiolabeling yield under mild conditions. High uptake and a high internalization ratio into LNCaP cells were observed in in vitro studies. In vivo studies showed that 68Ga-SC691 had favorable biodistribution properties and could specifically accumulate on PSMA-positive LNCaP xenografts visualized by micro-PET/CT. This radiotracer showed excellent PET imaging quality and comparable, if not higher, uptake in LNCaP xenografts than 68Ga-PSMA-11.
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Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Próstata/diagnóstico por imagen , Neoplasias de la Próstata/diagnóstico , Radiofármacos/farmacocinética , Animales , Antígenos de Superficie/metabolismo , Línea Celular Tumoral , Isótopos de Galio/administración & dosificación , Isótopos de Galio/farmacocinética , Radioisótopos de Galio/administración & dosificación , Radioisótopos de Galio/farmacocinética , Glutamato Carboxipeptidasa II/metabolismo , Humanos , Masculino , Ratones , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Próstata/patología , Neoplasias de la Próstata/patología , Radiofármacos/administración & dosificación , Distribución Tisular , Microtomografía por Rayos X/métodos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
This review presents data on dual conjugates of therapeutic and diagnostic action for targeted delivery to prostate cancer cells. The works of the last ten years on this topic were analyzed. The mail attention focuses on low-molecular-weight conjugates directed to the prostate-specific membrane antigen (PSMA); the comparison of high and low molecular weight PSMA-targeted conjugates was made. The considered conjugates were divided in the review into two main classes: diagnostic bimodal conjugates (which are containing two fragments for different types of diagnostics), theranostic conjugates (containing both therapeutic and diagnostic agents); also bimodal high molecular weight therapeutic conjugates containing two therapeutic agents are briefly discussed. The data of in vitro and in vivo studies for PSMA-targeted double conjugates available by the beginning of 2021 have been analyzed.