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Simple Summary: This study investigates the influence of various pharmacokinetic parameters on 177Lu-PSMA therapies via physical, biological, and statistical measures. Employing a clinically validated physiologically based pharmacokinetic (PBPK) model, realistic time–activity curves (TACs) in tumors, salivary glands, and kidneys are generated, allowing for the calculation of metrics such as AUC, dose, BED, and fBED. The results demonstrate the significant impact of multiple parameters on the measured outcomes. In addition to the great impact of administered ligand amount, tumor volume, and receptor density, other pharmacokinetic parameters such as rates of radiopharmaceutical association, internalization, and release were identified as key influencers. Notably, alterations in the parameters induced distinct modifications in TAC features, affecting radiobiological, pharmacokinetic, and statistical aspects. These insights contribute to advancing personalized treatment regimens by understanding the key contributions of various parameters towards improving therapeutic efficacy while minimizing radiation-related toxicities. Purpose: To investigate the impact of physiologically based pharmacokinetic (PBPK) parameters on physical, biological, and statistical measures in lutetium-177-labeled radiopharmaceutical therapies (RPTs) targeting the prostate-specific membrane antigen (PSMA). Methods: Using a clinically validated PBPK model, realistic time–activity curves (TACs) for tumors, salivary glands, and kidneys were generated based on various model parameters. These TACs were used to calculate the area-under-the-TAC (AUC), dose, biologically effective dose (BED), and figure-of-merit BED (fBED). The effects of these parameters on radiobiological, pharmacokinetic, time, and statistical features were assessed. Results: Manipulating PBPK parameters significantly influenced AUC, dose, BED, and fBED outcomes across four different BED models. Higher association rates increased AUC, dose, and BED values for tumors, with minimal impact on non-target organs. Increased internalization rates reduced AUC and dose for tumors and kidneys. Higher serum protein-binding rates decreased AUC and dose for all tissues. Elevated tumor receptor density and ligand amounts enhanced uptake and effectiveness in tumors. Larger tumor volumes required dosimetry adjustments to maintain efficacy. Setting the tumor release rate to zero intensified the impact of association and internalization rates, enhancing tumor targeting while minimizing the effects on salivary glands and kidneys. Conclusions: Optimizing PBPK parameters can enhance the efficacy of lutetium-177-labeled RPTs targeting PSMA, providing insights for personalized and effective treatment regimens to minimize toxicity and improve therapeutic outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Localized prostate cancer has a favorable prognosis and can be effectively treated with radiotherapy, as well as therapies that target hormone production and signaling. However, if the disease progresses past these treatments, treatment options are limited, and the disease often becomes fatal. In this review, we discuss the changes in treatment as prostate cancer develops, as well as the genetic mutations that accompany advanced prostate cancer. We highlight how these mutations can provide clinical opportunities to manipulate the DNA damage response for therapeutic gain using cancer-specific alterations in the genome and new therapeutic agents that are under development or entering clinical trials. Prostate cancers that progress despite androgen deprivation develop into castration-resistant prostate cancer, a fatal disease with few treatment options. In this review, we discuss the current understanding of prostate cancer subtypes and alterations in the DNA damage response (DDR) that can predispose to the development of prostate cancer and affect its progression. We identify barriers to conventional treatments, such as radiotherapy, and discuss the development of new therapies, many of which target the DDR or take advantage of recurring genetic alterations in the DDR. We place this in the context of advances in understanding the genetic variation and immune landscape of CRPC that could help guide their use in future treatment strategies. Finally, we discuss several new and emerging agents that may advance the treatment of lethal disease, highlighting selected clinical trials. [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen (PSMA)-based low-molecular-weight agents using beta(β)-particle-emitting radiopharmaceuticals is a new treatment paradigm for patients with metastatic castration-resistant prostate cancer. Although results have been encouraging, there is a need to improve the tumor residence time of current PSMA-based radiotherapeutics. Albumin-binding moieties have been used strategically to enhance the tumor uptake and retention of existing PSMA-based investigational agents. Previously, we developed a series of PSMA-based, β-particle-emitting, low-molecular-weight compounds. From this series, 177Lu-L1 was selected as the lead agent because of its reduced off-target radiotoxicity in preclinical studies. The ligand L1 contains a PSMA-targeting Lys-Glu urea moiety with an N-bromobenzyl substituent in the ε-amino group of Lys. Here, we structurally modified 177Lu-L1 to improve tumor targeting using two known albumin-binding moieties, 4-(p-iodophenyl) butyric acid moiety (IPBA) and ibuprofen (IBU), and evaluated the effects of linker length and composition. Six structurally related PSMA-targeting ligands (Alb-L1–Alb-L6) were synthesized based on the structure of 177Lu-L1. The ligands were assessed for in vitro binding affinity and were radiolabeled with 177Lu following standard protocols. All 177Lu-labeled analogs were studied in cell uptake and selected cell efficacy studies. In vivo pharmacokinetics were investigated by conducting tissue biodistribution studies for 177Lu-Alb-L2–177Lu-Alb-L6 (2 h, 24 h, 72 h, and 192 h) in male NSG mice bearing human PSMA+ PC3 PIP and PSMA− PC3 flu xenografts. Preliminary therapeutic ratios of the agents were estimated from the area under the curve (AUC0-192h) of the tumors, blood, and kidney uptake values. Compounds were obtained in >98% radiochemical yields and >99% purity. PSMA inhibition constants (Kis) of the ligands were in the ≤10 nM range. The long-linker-based agents, 177Lu-Alb-L4 and 177Lu-Alb-L5, displayed significantly higher tumor uptake and retention (p < 0.001) than the short-linker-bearing 177Lu-Alb-L2 and 177Lu-Alb-L3 and a long polyethylene glycol (PEG) linker-bearing agent, 177Lu-Alb-L6. The area under the curve (AUC0-192h) of the PSMA+ PC3 PIP tumor uptake of 177Lu-Alb-L4 and 177Lu-Alb-L5 were >4-fold higher than 177Lu-Alb-L2, 177Lu-Alb-L3, and 177Lu-Alb-L6, respectively. Also, the PSMA+ PIP tumor uptake (AUC0-192h) of 177Lu-Alb-L2 and 177Lu-Alb-L3 was ~1.5-fold higher than 177Lu-Alb-L6. However, the lowest blood AUC0-192h and kidney AUC0-192h were associated with 177Lu-Alb-L6 from the series. Consequently, 177Lu-Alb-L6 displayed the highest ratios of AUC(tumor)-to-AUC(blood) and AUC(tumor)-to-AUC(kidney) values from the series. Among the other agents, 177Lu-Alb-L4 demonstrated a nearly similar ratio of AUC(tumor)-to-AUC(blood) as 177Lu-Alb-L6. The tumor-to-blood ratio was the dose-limiting therapeutic ratio for all of the compounds. Conclusions: 177Lu-Alb-L4 and 177Lu-Alb-L6 showed high tumor uptake in PSMA+ tumors and tumor-to-blood ratios. The data suggest that linker length and composition can be modulated to generate an optimized therapeutic agent. [ABSTRACT FROM AUTHOR]

Targeted nanotheranostic systems offer significant benefits due to the integration of diagnostic and therapeutic functionality, promoting personalized medicine. In recent years, prostate-specific membrane antigen (PSMA) has emerged as an ideal theranostic target, fueling multiple new drug approvals and changing the standard of care in prostate cancer (PCa). PSMA-targeted nanosystems such as self-assembled nanoparticles (NPs), liposomal structures, water-soluble polymers, dendrimers, and other macromolecules are under development for PCa theranostics due to their multifunctional sensing and therapeutic capabilities. Herein, we discuss the significance and up-to-date development of "PSMA-targeted nanocarrier systems for radioligand imaging and therapy of PCa". The review also highlights critical parameters for designing nanostructured radiopharmaceuticals for PCa, including radionuclides and their chelators, PSMA-targeting ligands, and the EPR effect. Finally, prospects and potential for clinical translation is discussed. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate specific membrane antigen (PSMA) is a transmembrane protein that is highly expressed in prostate cancer cells. For patients with metastatic castration-resistant prostate cancer (mCRPC) who do not respond to conventional treatment, PSMA targeting radiopharmaceutical therapy (RPT) has recently been in the spotlight. [177Lu]Ludotadipep is a novel PSMA-targeting therapeutic agent designed with an albumin motif in order to increase the circulation time and uptake in the tumors. The safety and efficacy of [177Lu]Ludotadipep were evaluated through a phase I trial. [177Lu]Ludotadipep, which enables targeted delivery of beta-particle radiation to prostate tumor cells, had been suggested as a promising therapeutic option for mCRPC. From November 2020 to March 2022, a total of 30 patients were enrolled for single dose of [177Lu]Ludotadipep RPT, 6 subjects in each of the 5 different activity groups of 1.9 GBq, 2.8 GBq, 3.7 GBq, 4.6 GBq, and 5.6 GBq. [177Lu]Ludotadipep was administered via venous injection, and patients were hospitalized for three days to monitor for any adverse effects. Serum PSA levels were followed up at weeks 1, 2, 3, 4, 6, 8, and 12, and PSMA PET/CT with [18F]Florastamin was obtained at baseline and again at weeks 4 and 8. The subjects required positive PSMA PET/CT prior to [177Lu]Ludotadipep administration. Among the 29 subjects who received [177Lu]Ludotadipep, 36 treatment emergent adverse events (TEAEs) occurred in 17 subjects (58.6%) and 4 adverse drug reactions (ADRs) in 3 subjects (10.3%). Of the total 24 subjects who had full 12-week follow-up data, 16 (66.7%) showed decrease in PSA of any magnitude, and 9 (37.5%) showed a decrease in PSA by 50% or greater. A total of 5 of the 24 patients (20.8%) showed disease progression (PSA increase of 25% or higher from the baseline) at the 12th week following single dose of [177Lu]Ludotadipep. These data thus far suggest that [177Lu]Ludotadipep could be a promising RPT agent with low toxicity in mCRPC patients who have not been responsive to conventional treatments. [ABSTRACT FROM AUTHOR]

Prostate cancers that progress despite androgen deprivation develop into castration-resistant prostate cancer, a fatal disease with few treatment options. In this review, we discuss the current understanding of prostate cancer subtypes and alterations in the DNA damage response (DDR) that can predispose to the development of prostate cancer and affect its progression. We identify barriers to conventional treatments, such as radiotherapy, and discuss the development of new therapies, many of which target the DDR or take advantage of recurring genetic alterations in the DDR. We place this in the context of advances in understanding the genetic variation and immune landscape of CRPC that could help guide their use in future treatment strategies. Finally, we discuss several new and emerging agents that may advance the treatment of lethal disease, highlighting selected clinical trials.

166Ho-EDTMP is a major therapeutic agent which is widely used in bone palliation therapy. In this study, a 166Ho-EDTMP complex was prepared successfully using an in-house synthesized EDTMP ligand and 166HoCl3. Ho-166 chloride was obtained by thermal neutron irradiation (1 x 1013 ncm-2s-1) of natural Ho(NO3)3 samples (specific activity = 3-5 GBq/mg), dissolved in acidic media. The radiochemical purity of 166Ho-EDTMP was checked by ITLC (>99%) and stability studies in presence of human serum and final preparation were performed. The biodistribution of 166Ho-EDTMP and 166HoCl3 in wild-type rats was checked by scarification. SPECT imaging of 166Ho-EDTMP was also performed in wild-type rats. A comparative accumulation study for 166Ho-EDTMP and 166HoCl3 was performed for vital organs up to 48h. Significant bone accumulation (>70%) of the tracer in 48h was observed. [ABSTRACT FROM AUTHOR]

Theranostics are emerging as a pillar of cancer therapy that enable the use of single molecule constructs for diagnostic and therapeutic application. As poly adenosine diphosphate (ADP)-ribose polymerase 1 (PARP-1) is overexpressed in various cancer types, and is localized to the nucleus, PARP-1 can be safely targeted with Auger emitters to induce DNA damage in tumors. Here, we investigated a radioiodinated PARP inhibitor, [125I]KX1, and show drug target specific DNA damage and subsequent killing of BRCA1 and non-BRCA mutant ovarian cancer cells at sub-pharmacological concentrations several orders of magnitude lower than traditional PARP inhibitors. Furthermore, we demonstrated that viable tumor tissue from ovarian cancer patients can be used to screen tumor radiosensitivity ex-vivo, enabling the direct assessment of therapeutic efficacy. Finally, we showed tumors can be imaged by single-photon computed tomography (SPECT) with PARP theranostic, [123I]KX1, in a human ovarian cancer xenograft mouse model. These data support the utility of PARP-1 targeted radiopharmaceutical therapy as a theranostic option for PARP-1 overexpressing ovarian cancers. [ABSTRACT FROM AUTHOR]

(166)Ho-EDTMP is a major therapeutic agent which is widely used in bone palliation therapy. In this study, a (166)Ho-EDTMP complex was prepared successfully using an in-house synthesized EDTMP ligand and (166)HoCl(3). Ho-166 chloride was obtained by thermal neutron irradiation (1 Ã 10(13) ncm(â2)s(â1)) of natural Ho(NO(3))(3) samples (specific activity = 3â5 GBq/mg), dissolved in acidic media. The radiochemical purity of (166)Ho-EDTMP was checked by ITLC (>99%) and stability studies in presence of human serum and final preparation were performed. The biodistribution of (166)Ho-EDTMP and (166)HoCl(3) in wild-type rats was checked by scarification. SPECT imaging of (166)Ho-EDTMP was also performed in wild-type rats. A comparative accumulation study for (166)Ho-EDTMP and (166)HoCl(3) was performed for vital organs up to 48h. Significant bone accumulation (>70%) of the tracer in 48h was observed.