Development and validation of a high-performance thin-layer chromatography method for detection of sibutramine in dietary supplements.

INTRODUCTION: In the period between 1997 and 2010, sibutramine-containing drugs were widely prescribed for obesity and over-weight management. Due to safety concerns, in 2010 all medicines containing sibutramine were urgently withdrawn from the USA and European pharmaceutical market. Although sibutramine is no longer available in pharmaceutical products, there have been numerous reports of mislabeled weight-loss dietary supplements containing sibutramine.

[Sensitivity of colorectal cancer organoids to hyperthermic intraperitoneal chemotherapy with lobaplatin].

Objective: To investigate the sensitivity of tumor organoids derived from samples of colorectal cancer to lobaplatin and oxaliplatin hyperthermic perfusion in vitro and to assist clinical development of hyperthermic intraperitoneal chemotherapy. Method: Tumor samples and relevant clinical data were collected from patients with pathologically confirmed colorectal cancer in the Sixth Affiliated Hospital of Sun Yat-sen University from July 2021 to December 2022. Organoids were cultured and tumor tissue were passaged. In vitro hyperthermic perfusion experiments were performed on organoids with good viability. Firstly, 10 organoids were treated with oxaliplatin and lobaplatin at the following six concentrations: 1 000, 250, 62.5, 15.6, 3.9, and 0.98 µmol/L. The organoids were exposed to oxaliplatin at 42℃ for 30 minutes and to lobaplatin at 42℃ for 60 minutes. Dose-response curves of responses to in vitro hyperthermic perfusion with these two drugs were constructed and evaluated. Clinical doses of oxaliplatin and lobaplatin were further tested on 30 organoids. This testing revealed oxaliplatin was effective at 579 µmol/L at a hyperthermic perfusion temperature of 42℃ for 30 min and lobaplatin was effective at 240 µmol/L at a hyperthermic perfusion temperature of 42℃ for 60 minutes. Result: Thirty-two tumor organoids were cultured from samples of colorectal cancer. The median concentration required for oxaliplatin to eliminate 50% of tumor cells (IC50) was 577.45 µmol/L (IQR: 1846.09 µmol/L). The median IC50 for lobaplatin was 85.04 µmol/L (IQR: 305.01 µmol/L).The difference between the two groups was not statistically significant (Z=1.784, P=0.084). In seven of 10 organoids, lobaplatin showed a greater IC50 after in vitro hyperthermic perfusion than did oxaliplatin. Testing of 30 organoids with clinical doses of oxaliplatin and lobaplatin revealed that oxaliplatin achieved an average inhibition rate of 39.6% (95%CI: 32.1%‒47.0%), whereas the average rate of inhibition for lobaplatin was 89.7% (95%CI: 87.0%‒92.3%): this difference is statistically significant (t=‒15.282, P<0.001). Conclusion: The rate of inhibition achieved by hyperthermic perfusion of lobaplatin in vitro is better than that achieved by hyperthermic perfusion with oxaliplatin. Lobaplatin is more effective than oxaliplatin when administered by hyperthermic intraperitoneal perfusion and therefore has the potential to replace oxaliplatin in this setting.

A prospective study on the early evaluation of response to androgen receptor-targeted agents with 11C-Choline, 68Ga-PSMA, and 18F-FACBC PET in metastatic castration-resistant prostate cancer: a single-center experience.

BACKGROUND: The early identification of responsive and resistant patients to androgen receptor-targeting agents (ARTA) in metastatic castration-resistant prostate cancer (mCRPC) is not completely possible with prostate-specific antigen (PSA) assessment and conventional imaging. Considering its ability to determine metabolic activity of lesions, positron emission tomography (PET) assessment might be a promising tool. PATIENTS AND METHODS: We carried out a monocentric prospective study in patients with mCRPC treated with ARTA to evaluate the role of different PET radiotracers: 49 patients were randomized to receive 11C-Choline, Fluorine 18 fluciclovine (anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid - FACBC) (18F-FACBC), or Gallium-68-prostate-specific-membrane-antigen (68Ga-PSMA) PET, one scan before therapy and one 2 months later. The primary aim was to investigate the performance of three novel PET radiotracers for the early evaluation of response to ARTA in metastatic CRPC patients; the outcome evaluated was biochemical response (PSA reduction ≥50%). The secondary aim was to investigate the prognostic role of several semiquantitative PET parameters and their variations with the different radiotracers in terms of biochemical progression-free survival (bPFS) and overall survival (OS). The study was promoted by the Italian Department of Health (code RF-2016-02364809). RESULTS: Regarding the primary endpoint, at log-rank test a statistically significant correlation was found between metabolic tumor volume (MTV) (P = 0.018) and total lesion activity (TLA) (P = 0.025) percentage variation among the two scans with 68Ga-PSMA PET and biochemical response. As for the secondary endpoints, significant correlations with bPFS were found for 68Ga-PSMA total MTV and TLA at the first scan (P = 0.001 and P = 0.025, respectively), and MTV percentage variation (P = 0.031). For OS, statistically significant correlations were found for different 68Ga-PSMA and 18F-FACBC parameters and for major maximum standardized uptake value at the first 11C-Choline PET scan. CONCLUSIONS: Our study highlighted that 11C-Choline, 68Ga-PSMA, and 18F-FACBC semiquantitative PET parameters and their variations present a prognostic value in terms of OS and bPFS, and MTV and TLA variations with 68Ga-PSMA PET a correlation with biochemical response, which could help to assess the response to ARTA.

Comparison of target agent treatment strategies for platinum-resistant recurrent ovarian cancer: A Bayesian network meta-analysis.

BACKGROUND: We aimed to compare 7 newer immunotherapies and targeted therapies for platinum-resistant relapsed ovarian cancer. METHODS: We conducted a comprehensive search of PubMed, EMBASE, and Cochrane Library electronic databases for phase III trials involving platinum-resistant recurrent ovarian cancer (PRrOC) patients treated with immunotherapy or targeted therapy in combination with chemotherapy. The quality of the included trials was assessed using the GRADE method. The primary outcome of comparison was progression-free survival, and secondary outcomes included overall survival and safety. RESULTS: This analysis included 7 randomized phase III controlled trials, encompassing 2485 PRrOC patients. Combining bevacizumab plus chemotherapy and lurbinectedin demonstrated statistically significant differences in progression-free survival compared to all other regimens of interest. However, no statistically significant differences were observed in the overall survival. Nivolumab and mirvetuximab exhibited fewer serious adverse events than the other regimens of interest. CONCLUSIONS: Our findings indicate that bevacizumab combined with chemotherapy and lurbinectedin monotherapy has significant efficacy in patients with PRrOC. For patients with PRrOC who have exhausted treatment options, nivolumab and mirvetuximab may be considered as alternatives because of their better safety profiles.

Structure-activity relationships of aniline-based squaraines for distinguishable staining and bright two-photon fluorescence bioimaging in plant cells.

An organelle-selective vision provides insights into the physiological response of plants and crops to environmental stresses in sustainable agriculture ecosystems. Biological applications often require two-photon excited fluorophores with low phototoxicity, high brightness, deep penetration, and tuneable cell entry. We obtained three aniline-based squaraines (SQs) tuned from hydrophobic to hydrophilic characteristics by modifying terminal pendant groups and substituents, and investigated their steady-state absorption and far-red-emitting fluorescence properties. The SQs exhibited two-photon absorption (2PA) ranging from 750 to 870 nm within the first biological spectral window; their structure-property relationships, corresponding to the 2PA cross sections (δ2PA), and structure differences were demonstrated. The maximum δ2PA value was ∼1220 GM at 800 nm for hydrophilic SQ3. Distinct biological staining efficiency and selective SQ bioimaging were evaluated utilizing the onion epidermal cell model. Contrary to the hydrophobic SQ1 results in the onion epidermal cell wall, amphiphilic SQ2 tagged the vacuole and nucleus and SQ3 tagged the vacuole. Distinguishable staining profiles in the roots and leaves were achieved. We believe that this study is the first to demonstrate distinct visualisation efficiency induced by the structure differences of two-photon excited SQs. Our results can help establish the versatile roles of novel near-infrared-emitting SQs in biological applications.

Detection of Adenocarcinoma of the Colon on 18 F-Fluciclovine PET/CT.

ABSTRACT: An 85-year-old man with prostate cancer and de novo bone metastases was treated with hormonal therapy with resolution of bone lesions, improved primary disease, and improved serum tumor markers. Although on hormonal therapy, biochemical recurrence prompted performance of 18 F-fluciclovine PET/CT. Fluciclovine PET/CT revealed primary prostate cancer progression with incidental note of avid foci in the colon for which colonoscopy was recommended. Colonoscopy with biopsy was performed with pathology revealing primary colon adenocarcinoma. Before reinitiation of prostate cancer therapy, segmental colon resection was performed with pathology positive for additional sites of colon cancer.

Tumor-Targeted Squaraine Dye for Near-Infrared Fluorescence-Guided Photodynamic Therapy.

Many efforts have been made to develop near-infrared (NIR) fluorescent dyes with high efficiency for the NIR laser-induced phototherapy of cancer. However, the low tumor targetability and high nonspecific tissue uptake of NIR dyes in vivo limit their applications in preclinical cancer imaging and therapy. Among the various NIR dyes, squaraine (SQ) dyes are widely used due to their high molar extinction coefficient, intense fluorescence, and excellent photostability. Previously, benzoindole-derived SQ (BSQ) was prepared by incorporating carboxypentyl benzoindolium end groups into a classical SQ backbone, followed by conjugating with cyclic RGD peptides for tumor-targeted imaging. In this study, we demonstrate that the structure-inherent tumor-targeting BSQ not only shows a high fluorescence quantum yield in serum but also exhibits superior reactive oxygen species (ROS) generation capability under the 671 nm laser irradiation for effective photodynamic therapy (PDT) in vitro and in vivo. Without targeting ligands, the BSQ was preferentially accumulated in tumor tissue 24 h post-injection, which was the optimal timing of the laser irradiation to induce increments of ROS production. Therefore, this work provides a promising strategy for the development of photodynamic therapeutic SQ dyes for targeted cancer therapy.

Design and Synthesis of Novel Squaraine-Based Fluorescent Probe for Far-Red Detection of Chymotrypsin Enzyme.

Chymotrypsin, a crucial enzyme in human digestion, catalyzes the breakdown of milk proteins, underscoring its significance in both health diagnostics and dairy quality assurance. Addressing the critical need for rapid, cost-effective detection methods, we introduce a groundbreaking approach utilizing far-red technology and HOMO-Förster resonance energy transfer (FRET). Our novel probe, SQ-122 PC, features a unique molecular design that includes a squaraine dye (SQ), a peptide linker, and SQ moieties synthesized through solid-phase peptide synthesis. Demonstrating a remarkable quenching efficiency of 93.75% in a tailored H2O:DMSO (7:3) solvent system, our probe exhibits absorption and emission properties within the far-red spectrum, with an unprecedented detection limit of 0.130 nM. Importantly, our method offers unparalleled selectivity towards chymotrypsin, ensuring robust and accurate enzyme detection. This pioneering work underscores the immense potential of far-red-based homo-FRET systems in enabling the sensitive and specific detection of chymotrypsin enzyme activity. By bridging the gap between cutting-edge technology and biomedical diagnostics, our findings herald a new era of enzyme sensing, promising transformative advancements in disease diagnosis and dairy quality control.

Fused Azulenyl Squaraine Derivatives Improve Phototheranostics in the Second Near-Infrared Window by Concentrating Excited State Energy on Non-Radiative Decay Pathways.

The second near-infrared (NIR-II) theranostics offer new opportunities for precise disease phototheranostic due to the enhanced tissue penetration and higher maximum permissible exposure of NIR-II light. However, traditional regimens lacking effective NIR-II absorption and uncontrollable excited-state energy decay pathways often result in insufficient theranostic outcomes. Herein a phototheranostic nano-agent (PS-1 NPs) based on azulenyl squaraine derivatives with a strong NIR-II absorption band centered at 1092 nm is reported, allowing almost all absorbed excitation energy to dissipate through non-radiative decay pathways, leading to high photothermal conversion efficiency (90.98 %) and strong photoacoustic response. Both in vitro and in vivo photoacoustic/photothermal therapy results demonstrate enhanced deep tissue cancer theranostic performance of PS-1 NPs. Even in the 5 mm deep-seated tumor model, PS-1 NPs demonstrated a satisfactory anti-tumor effect in photoacoustic imaging-guided photothermal therapy. Moreover, for the human extracted tooth root canal infection model, the synergistic outcomes of the photothermal effect of PS-1 NPs and 0.5 % NaClO solution resulted in therapeutic efficacy comparable to the clinical gold standard irrigation agent 5.25 % NaClO, opening up possibilities for the expansion of NIR-II theranostic agents in oral medicine.

Two Hematological Markers Predicting the Efficacy and Prognosis of Neoadjuvant Chemotherapy Using Lobaplatin Against Triple-Negative Breast Cancer.

BACKGROUND: Our previous work indicated that the addition of lobaplatin to combined therapy with taxane and anthracycline can improve the pathological complete response rate of neoadjuvant therapy for triple-negative breast cancer (TNBC) and lengthen long-term survival significantly, but the therapeutic markers of this regimen are unclear. METHODS: Eighty-three patients who met the inclusion criteria were included in this post hoc analysis. We analyzed the association between platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) before neoadjuvant chemotherapy with the efficacy and prognosis after treatment with docetaxel, epirubicin, and lobaplatin neoadjuvant chemotherapy regimen. χ2 test and Cox regression were used to analyze the association between PLR and NLR with total pathologic complete response (tpCR), as well as the association between PLR and NLR with event-free survival (EFS) and overall survival (OS), respectively. RESULTS: The tpCR rate in the PLR- group was 49.0% (25/51), which was significantly higher than that in the PLR+ group (25.0% [8/32], P = .032). The tpCR rate in the NLR- group was 49.1% (26/53), which was significantly higher than that in the NLR+ group (23.3% [7/30], P = .024). The tpCR rate of the PLR-NLR- (PLR- and NLR-) group was 53.7% (22/41), which was significantly higher than that of the PLR+/NLR+ (PLR+ or/and NLR+) group (26.1% [11/42]; P = .012). EFS and OS in the NLR+ group were significantly shorter than those in the NLR- group (P = .028 for EFS; P = .047 for OS). Patients in the PLR-NLR- group had a longer EFS than those in the PLR+/NLR+ group (P = .002). CONCLUSION: PLR and NLR could be used to predict the efficacy of neoadjuvant therapy with the taxane, anthracycline, and lobaplatin regimen for patients with TNBC, as patients who had lower PLR and NLR values had a higher tpCR rate and a better long-term prognosis.

Evaluating appropriateness of 18F-fluciclovine PET/CT relative to standard of care imaging guidelines and the impact of ADT on positivity: a prospective study in 62 Veterans Administration patients at a single institution.

BACKGROUND: According to the National Comprehensive Cancer Network Guidelines, 18F-fluciclovine PET/CT is considered appropriate after negative standard of care (SOC) imaging. OBJECTIVE: To prospectively compare 18F-fluciclovine to SOC imaging, investigate whether it should be done when SOC imaging is (+), and evaluate its detection rate in patients receiving androgen deprivation therapy. METHODS: We recruited 57 prostate cancer patients with biochemical recurrence with 18F-fluciclovine PET/CT and SOC imaging within 30 days. Prostate-specific antigen (PSA) level, Gleason score (GS), history of radical prostatectomy (RP), radiation therapy (RT) or hormone therapy (HT) were reviewed. RESULTS: The 57 patients had a median PSA of 2.6 and average GS of 7.4; 27 (47.4%) had RP, 28 (49.1%) had RT, 1 (1.75%) had HT and 1 (1.75%) observation only. 18F-fluciclovine identified disease recurrence in 45/57 patients (78.9%), including oligometastasis in 18/45 (40%). SOC imaging identified recurrent disease in 12/57 patients (21.1%) while 18F-fluciclvoine identified additional sites of disease in 11/12 (91.7%). The (+) 18F-fluciclovine studies had a median PSA 2.6 ng/ml compared to 6.0 ng/ml in the (+) SOC studies. CONCLUSION: 18F-fluciclovine was superior to SOC imaging for lesion detection, identification of oligometastasis and identification of additional sites of disease.

Pharmacological treatment of obesity in adults in Norway 2004-2022.

AIMS: To describe trends in the use of anti-obesity drugs in Norway during the period 2004-2022. MATERIALS AND METHODS: We assessed the annual utilization of any available drug indicated for obesity recorded in the nationwide Norwegian Prescribed Drug Register for adults (age 18-79 years) from 1 January 2004 to 31 December 2022. Prevalence was stratified by sex and age group (18-29 years and 10-year age groups thereafter). Additional analyses were performed in individuals initiating treatment with an anti-obesity drug and on the cost of the anti-obesity drugs since 2017. RESULTS: The prevalence of anti-obesity drug use decreased from 2009, when sibutramine and rimonabant were withdrawn from the market, and increased again after the approval of bupropion-naltrexone in 2017 and liraglutide in 2018. The use of the peripheral-acting anti-obesity drug orlistat decreased from 2004. In 2022, 1.04% of the adult Norwegian population (72.8% women) filled at least one prescription of bupropion-naltrexone, 0.91% used liraglutide (Saxenda; 74.2% women), and semaglutide without reimbursement was used by 0.68% (76.7% women). The prevalence increased with age, peaking in the age group 50 to 59 years, and decreased in older age groups. From 2017 to 2022, 2.8% of the adult residents initiated treatment with an anti-obesity drug. The total sale of those drugs increased from 1.1 million euros in 2017 to 91.8 million euros in 2022. CONCLUSIONS: The use of anti-obesity drugs in Norway has increased substantially in recent years, especially among women aged 40 to 59 years. Changes in availability and reimbursement have influenced the use of these drugs in recent years.

An on-off-on fluorescent probe for the detection of glyphosate based on a Cu2+-assisted squaraine dye sensor.

The herbicide glyphosate, N-(phosphonomethyl)glycine, has been widely used in the past 40 years, and has had many adverse effects on human health. Here, we constructed a convenient "on-off-on" fluorescent platform for detection of glyphosate via Cu2+ modulated squaraine dye fluorescence quenching. The squaraine dye F-0 exhibited strong fluorescence, which could be quenched by the addition of Cu2+. However, the addition of glyphosate restored the fluorescence intensity of F-0 due to the formation of a Cu2+-glyphosate complex. F-0 was utilized as a fluorescent probe for the quantitative detection of glyphosate, with the lowest detection limit of 13.16 nmol L-1. Furthermore, this method demonstrated high selectivity and anti-interference capabilities. The successful monitoring of glyphosate in real samples was achieved using this detection strategy.

Is cognitive behavioral therapy more effective than pharmacotherapy for binge spectrum disorders? A systematic review and meta-analysis.

OBJECTIVES: Binge spectrum disorders are prevalent worldwide. Psychiatric and medical comorbidities are common, and societal costs are significant. Evidence-based treatment remains underutilized. Cognitive behavioral therapy is the recommended first-line treatment, but pharmacotherapy may be easier to access. INTERVENTIONS: Meta-analytic evidence directly comparing cognitive behavioral therapy with pharmacotherapy is lacking. We aimed to compare the effects of cognitive behavioral therapy interventions with any pharmacological treatment for binge spectrum disorders. We searched PubMed, Embase, CENTRAL, ClinicalTrials.gov and reference lists for randomized controlled trials comparing cognitive behavioral therapy with any pharmacotherapy for bulimia nervosa/binge eating disorder and performed pairwise meta-analytic evaluations. PRIMARY OUTCOMES: Primary outcomes are remission and frequency of binges. Secondary outcomes are frequency of purges, response, eating disorder psychopathology, weight/body mass index, depression, anxiety, quality of life and dropouts. RESULTS: Eleven randomized controlled trials comparing cognitive behavioral therapy with fluoxetine/imipramine/desipramine/methylphenidate/sibutramine were identified (N = 531). Cognitive behavioral therapy was superior to antidepressants in terms of remission, frequency of binges and eating disorder psychopathology. There were no statistically significant differences for any of the individual cognitive behavioral therapy vs drug comparisons in terms of response/depression/anxiety/weight/quality of life/dropouts. Cognitive behavioral therapy was not superior to sibutramine/methylphenidate for the primary outcomes. CONCLUSIONS: Data are scarce, comparisons underpowered and, considering the inherent methodological limitations of psychotherapy trials, questions arise regarding the presumed superiority of cognitive behavioral therapy. Further research is needed.

Cardiogenic shock in a 28-year-old woman associated with sibutramine use.

A 28-year-old woman collapsed in her home, and her companion rushed to call emergency services. Upon arrival, a physician performed CPR and endotracheal intubation, successfully restoring her voluntary heart rhythm. However, while en route to the hospital, ventricular fibrillation recurred. Despite the restoration of her voluntary rhythm through electrical defibrillation, she remained in a comatose state, which eventually led to multiple organ failures. Family members revealed that she had a 2-month history of taking diet pills. Histological examination revealed cardiomyocyte necrosis, contraction band necrosis, interstitial hemorrhage, collagen deposition, interstitial fiber proliferation, and myofiber remodeling. Analysis of blood and urine using GC-MS and LC-MS detected sibutramine and its primary metabolites, M1 and M2, which were consistent with the composition of the medication she was taking. The deceased was in good health with no underlying heart disease. The above information confirmed that the cause of her death was sibutramine.

Initial Experience with the Radiotracer 18F-Fluciclovine PET/CT in Ovarian Cancer.

OBJECTIVE: Early and accurate staging of ovarian cancer is paramount to disease survival. Conventional imaging including FDG PET/CT are limited in the evaluation of small metastatic lesions. 18F-Fluciclovine has minimal urine and bowel excretion allowing optimal visualization of the abdomen and pelvis. This study examines 18F-fluciclovine uptake in known primary and recurrent ovarian cancer. METHODS: Seven patients with a confirmed diagnosis of epithelial ovarian cancer underwent 18F-fluciclovine PET/CT imaging. Forty-one (41) lesions were identified with 18F-fluciclovine and confirmed to be true positive (n = 41). We aim to explore if 18F-fluciclovine uptake in ovarian lesions were greater than background uptake of bone marrow, blood pool, and bladder. Quantification analysis was performed to determine max and mean standard uptake values (SUVmax and SUVmean) of known and suspected lesions compared to SUVmean uptake of background structures. RESULTS: 18F-Fluciclovine demonstrated 100% sensitivity (41/41) for uptake in known ovarian lesions. The average SUVmax (±SD) uptake of known ovarian lesions was 5.9 (±2.6) and 5.1 (±2.0) on early and delayed images, respectively. The average tumor SUVmax to SUVmean of background (±SD) (T:B) ratios on early and delay were 1.9 (±0.8), 2.1 (±0.9) for marrow; 3.8 (±1.8), 3.4 (±1.5) for aorta; and 8.4 (±4.3), 1.5 (±1.7) for bladder, respectively. CONCLUSION: 18F-Fluciclovine uptake in malignant ovarian lesions was above background levels suggesting its feasibility in the imaging of ovarian cancer. Due to increasing tracer washout via the urinary bladder over time, early imaging at 4 min post injection is favorable.

Thiolation for Enhancing Photostability of Fluorophores at the Single-Molecule Level.

Fluorescent probes are essential for single-molecule imaging. However, their application in biological systems is often limited by the short photobleaching lifetime. To overcome this, we developed a novel thiolation strategy for squaraine dyes. By introducing thiolation of the central cyclobutene of squaraine (thio-squaraine), we observed a ≈5-fold increase in photobleaching lifetime. Our single-molecule data analysis attributes this improvement to improved photostability resulting from thiolation. Interestingly, bulk measurements show rapid oxidation of thio-squaraine to its oxo-analogue under irradiation, giving the perception of inferior photostability. This discrepancy between bulk and single-molecule environments can be ascribed to the factors in the latter, including larger intermolecular distances and restricted mobility, which reduce the interactions between a fluorophore and reactive oxygen species produced by other fluorophores, ultimately impacting photobleaching and photoconversion rate. We demonstrate the remarkable performance of thio-squaraine probes in various imaging buffers, such as glucose oxidase with catalase (GLOX) and GLOX+trolox. We successfully employed these photostable probes for single-molecule tracking of CD56 membrane protein and monitoring mitochondria movements in live neurons. CD56 tracking revealed distinct motion states and the corresponding protein fractions. This investigation is expected to propel the development of single-molecule imaging probes, particularly in scenarios where bulk measurements show suboptimal performance.

Cost-Effectiveness Modeling of Prostate-Specific Membrane Antigen Positron Emission Tomography with Piflufolastat F 18 for the Initial Diagnosis of Patients with Prostate Cancer in the United States.

BACKGROUND AND OBJECTIVES: Piflufolastat F 18 is a novel prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) radiotracer that is superior to standard of care (SOC) imaging for the initial staging of prostate cancer and the detection of biochemical recurrence. As piflufolastat F 18 has been approved in the United States (US) for this indication, this modeling study assessed the cost effectiveness of piflufolastat F 18 versus fluciclovine F-18, gallium68-PSMA-11 (PSMA 11), and SOC imaging (a mix of bone scans, computed tomography, and magnetic resonance imaging) for the diagnosis and staging of prostate cancer from a US healthcare system perspective. PERSPECTIVE: A US third-party payer perspective was used, which for this population reflects a mix of commercial and Medicare, considering only direct healthcare costs. SETTING: This study utilized a tertiary healthcare setting. METHODS: A decision tree was used to map the diagnostic/treatment pathway, consisting of the proportion of patients with local, regional, distant, or no disease; prostate-specific antigen (PSA) ≤ 1.0 or > 1.0; and accuracy of imaging modalities. A Markov model predicted the long-term outcomes of disease progression according to treatment decisions. Inputs to the model were informed by data from the OSPREY and CONDOR clinical trials, public data, and the literature. Treatment mix included active surveillance, radiation therapy, prostatectomy, androgen deprivation therapy (ADT), and radiation therapy + ADT, informed by expert opinion. Outcomes included life-years (LY), quality-adjusted life-years (QALY), and the incremental cost-effectiveness ratio (ICER). All costs were reported in 2021 US dollars, using the US Bureau of Labor Statistics Consumer Price Index. A willingness-to-pay (WTP) threshold of $150,000 was considered cost effective, consistent with the upper range used as the standard for price benchmarks by the Institute for Clinical and Economic Review. The robustness of the base-case results was assessed in deterministic and probabilistic sensitivity analyses. RESULTS: Over a lifetime horizon, piflufolastat F 18 had the greatest effectiveness in terms of LYs (6.80) and QALYs (5.33); for the comparators, LYs ranged from 6.58 (SOC) to 6.76 (PSMA 11) and QALYs ranged from 5.12 (SOC) and 5.30 (PSMA 11). Piflufolastat F 18 was more cost effective compared with fluciclovine F 18, PSMA 11, and SOC, with ICERs of $21,122, $55,836, and $124,330 per QALY gained, respectively. Piflufolastat F 18 was associated with the greatest net monetary benefit ($627,918) compared with the other options at a WTP threshold of $150,000. The results of the deterministic and probabilistic sensitivity analyses supported the robustness of the base-case results. CONCLUSIONS: This study suggests that piflufolastat F 18 is a cost-effective diagnostic option for men with prostate cancer in the US, with higher associated LY, QALY, and greater net monetary benefit than fluciclovine F 18, PSMA 11, and SOC imaging.

Photophysical Characterization and Biointeractions of NIR Squaraine Dyes for in Vitro and in Vivo Bioimaging.

The increasing demand for reliable near-infrared (NIR) probes exhibiting enduring fluorescence in living systems and facile compatibility with biomolecules such as peptides, antibodies or proteins is driven by the increasing use of NIR imaging in clinical diagnostics. To address this demand, a series of carboxy-functionalized unsymmetrical squaraine dyes (SQ-27, SQ-212, and SQ-215) along with non-carboxy-functionalized SQ-218 absorbing and emitting in the NIR wavelength range were designed and synthesized followed by photophysical characterization. This study focused on the impact of structural variations in the alkyl chain length, carboxy functionality positioning, and spacer chain length on dye aggregation and interaction with bovine serum albumin (BSA) as a model protein. In phosphate buffer (PB), the absorption intensity of the dyes markedly decreased accompanied by pronounced shoulders indicative of dye aggregation, and complete fluorescence quenching was seen in contrast to organic solvents. However, in the presence of BSA in PB, there was a enhancement in absorption intensity while regaining the fluorescence coupled with a remarkable increase in the intensity with increasing BSA concentrations, signifying the impact of dye-BSA interactions on preventing aggregation. Further analysis of Job's plot unveiled a 2:1 interaction ratio between BSA and all dyes, while the binding studies revealed a robust binding affinity (Ka) in the order of 107/mol. SQ-212 and SQ-215 were further tested for their in vitro and in vivo imaging capabilities. Notably, SQ-212 demonstrated nonpermeability to cells, while SQ-215 exhibited easy penetration and prominent cytoplasmic localization in in vitro studies. Injection of the dyes into laboratory mice showcased their efficacy in visualization, displaying stable and intense fluorescence in tissues without toxicity, organ damage, or behavioral changes. Thus, SQ-212 and SQ-215 are promising candidates for imaging applications, holding potential for noninvasive cellular and diagnostic imaging as well as biomarker detection when coupled with specific vectors in living systems.

Effect of hydrophilicity-imparting substituents on exciton delocalization in squaraine dye aggregates covalently templated to DNA Holliday junctions.

Molecular aggregates exhibit emergent properties, including the collective sharing of electronic excitation energy known as exciton delocalization, that can be leveraged in applications such as quantum computing, optical information processing, and light harvesting. In a previous study, we found unexpectedly large excitonic interactions (quantified by the excitonic hopping parameter Jm,n) in DNA-templated aggregates of squaraine (SQ) dyes with hydrophilic-imparting sulfo and butylsulfo substituents. Here, we characterize DNA Holliday junction (DNA-HJ) templated aggregates of an expanded set of SQs and evaluate their optical properties in the context of structural heterogeneity. Specifically, we characterized the orientation of and Jm,n between dyes in dimer aggregates of non-chlorinated and chlorinated SQs. Three new chlorinated SQs that feature a varying number of butylsulfo substituents were synthesized and attached to a DNA-HJ via a covalent linker to form adjacent and transverse dimers. Various characteristics of the dye, including its hydrophilicity (in terms of log Po/w) and surface area, and of the substituents, including their local bulkiness and electron withdrawing capacity, were quantified computationally. The orientation of and Jm,n between the dyes were estimated using a model based on Kühn-Renger-May theory to fit the absorption and circular dichroism spectra. The results suggested that adjacent dimer aggregates of all the non-chlorinated and of the most hydrophilic chlorinated SQ dyes exhibit heterogeneity; that is, they form a mixture of dimers subpopulations. A key finding of this work is that dyes with a higher hydrophilicity (lower log Po/w) formed dimers with smaller Jm,n and large center-to-center dye distance (Rm,n). Also, the results revealed that the position of the dye in the DNA-HJ template, that is, adjacent or transverse, impacted Jm,n. Lastly, we found that Jm,n between symmetrically substituted dyes was reduced by increasing the local bulkiness of the substituent. This work provides insights into how to maintain strong excitonic coupling and identifies challenges associated with heterogeneity, which will help to improve control of these dye aggregates and move forward their potential application as quantum information systems.