Search Results (8)

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 (AUC_0-192h) of the tumors, blood, and kidney uptake values. Compounds were obtained in >98% radiochemical yields and >99% purity. PSMA inhibition constants (K_is) 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 (AUC_0-192h) 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 (AUC_0-192h) of ¹⁷⁷Lu-Alb-L2 and ¹⁷⁷Lu-Alb-L3 was ~1.5-fold higher than ¹⁷⁷Lu-Alb-L6. However, the lowest blood AUC_0-192h and kidney AUC_0-192h 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. Full article

This article analyses competences 4.0 models created in the context of the concept of Industry 4.0. A literature review and bibliometric analyses were used to show the semantic shift of this concept over time. The results show that the 4.0 competences created in the context of Industry 4.0 assume that the skills they represent are needed in the labor market. Moreover, in most cases, analyses of competences 4.0 are carried out considering separate perspectives by researchers representing different scientific disciplines. Refining and fine-tuning a universal and detailed model of competences 4.0 is strongly recommended to bridge the gap between other scientific disciplines. Furthermore, this article presents competences 4.0 from a much broader perspective, including linguistic competences that stem from the wider domain of the ability to communicate within social competences. Linguistic competences are also interrelated with some aspects of cognitive competences. This approach makes this study completely novel and aims to present the most comprehensive and universal 4.0 model to date. Full article

The chemokine receptor 4 (CXCR4) is a promising diagnostic and therapeutic target for the management of various cancers. CXCR4 has been utilized in immunotherapy, targeted drug delivery, and endoradiotherapy. Poly(amidoamine) [PAMAM] dendrimers are well-defined polymers with unique properties that have been used in the fabrication of nanomaterials for several biomedical applications. Here, we describe the formulation and pharmacokinetics of generation-5 CXCR4-targeted PAMAM (G5-X4) dendrimers. G5-X4 demonstrated an IC₅₀ of 0.95 nM to CXCR4 against CXCL12-Red in CHO-SNAP-CXCR4 cells. Single-photon computed tomography/computed tomography imaging and biodistribution studies of ¹¹¹In-labeled G5-X4 showed enhanced uptake in subcutaneous U87 glioblastoma tumors stably expressing CXCR4 with 8.2 ± 2.1, 8.4 ± 0.5, 11.5 ± 0.9, 10.4 ± 2.6, and 8.8 ± 0.5% injected dose per gram of tissue at 1, 3, 24, 48, and 120 h after injection, respectively. Specific accumulation of [¹¹¹In]G5-X4 in CXCR4-positive tumors was inhibited by the peptidomimetic CXCR4 inhibitor, POL3026. Our results demonstrate that while CXCR4 targeting is beneficial for tumor accumulation at early time points, differences in tumor uptake are diminished over time as passive accumulation takes place. This study further confirms the applicability of PAMAM dendrimers for imaging and therapeutic applications. It also emphasizes careful consideration of image acquisition and/or treatment times when designing dendritic nanoplatforms for tumor targeting. Full article

We have synthesized a series of 10 new, PSMA-targeted, near-infrared imaging agents intended for use in vivo for fluorescence-guided surgery (FGS). Compounds were synthesized from the commercially available amine-reactive active NHS ester of DyLight800. We altered the linker between the PSMA-targeting urea moiety and the fluorophore with a view to improve the pharmacokinetics. Chemical yields for the conjugates ranged from 51% to 86%. The K_i values ranged from 0.10 to 2.19 nM. Inclusion of an N-bromobenzyl substituent at the ε-amino group of lysine enhanced PSMA⁺ PIP tumor uptake, as did hydrophilic substituents within the linker. The presence of a polyethylene glycol chain within the linker markedly decreased renal uptake. In particular, DyLight800-10 demonstrated high specific uptake relative to background signal within kidney, confirmed by immunohistochemistry. These compounds may be useful for FGS in prostate, renal or other PSMA-expressing cancers. Full article

Background and objectives: Many mediators and cytokines are involved in the pathogenesis of osteoarthritis (OA). Some of these cytokines are spontaneously expressed by cultured fibroblast-like synoviocytes. Therefore, using serum samples, the efficacy and the effects of avocado/soy unsaponifiables, ASU, (Arthrocen) on cytokine changes were assessed in patients with knee OA (KOA). Materials and Methods: Experimental procedure: A randomized, double-blind, placebo-controlled clinical trial was conducted on patients with a diagnosis of mild to moderate OA who received either Arthrocen 300 mg/day (n = 61) or placebo (n = 58) for 3 months. Data collection was performed using questionnaires including the Western Ontario and McMaster Universities osteoarthritis index (WOMAC), 20-item short form survey (SF-20), Lequesne index of severity for osteoarthritis of the knee (LISOK), and three visual analog scales (VASs) as pain quality indices. The serum levels of interleukins 2 (IL-2), IL-4, IL-10, IL-17α, and TNF-α were measured using an ELISA reader. Results: Both quality of life indices, pain sensation and scored by specialists (as VASs), respectively, including WOMAC and SF-20, as well as joint dysfunctionality symptoms assessed by physicians were significantly improved (p < 0.05) in OA patients receiving Arthrocen. The serum levels of anti-inflammatory interleukins 4 and 10 were also augmented, while levels of inflammatory IL-17 and TNF-ɑ cytokines were decreased significantly (p < 0.05) compared with the control groups during the 3- and 6-month treatment. Conclusions: Arthrocen consumption may increase the quality of life in OA patients through amelioration of inflammation and improvement of functional activities without any adverse effects in the long term. Full article

Radiotherapy is a common approach for the treatment of a wide variety of cancer types. Available data indicate that nanoparticles can enhance the effect of radiotherapy. We report the use of human mesenchymal stem cells to selectively deliver gold nanoparticles (GNPs) to MDA-MB-231 breast tumor xenografts in mice for the purpose of enhancing the effect of radiation therapy. Targeted delivery of GNPs to the tumor site, followed by irradiation of the tumor, enabled control of tumor growth. The results indicate that tumor-selective GNP delivery by human mesenchymal stem cells may represent a viable way to enhance the effectiveness of radiotherapy. Full article

Prostate-Specific Membrane Antigen (PSMA) is an established biomarker for the imaging and experimental therapy of prostate cancer (PCa), as it is strongly upregulated in high-grade primary, androgen-independent, and metastatic lesions. Here, we report on the development and functional characterization of recombinant single-chain Fv (scFv) and Fab fragments derived from the 5D3 PSMA-specific monoclonal antibody (mAb). These fragments were engineered, heterologously expressed in insect S2 cells, and purified to homogeneity with yields up to 20 mg/L. In vitro assays including ELISA, immunofluorescence and flow cytometry, revealed that the fragments retain the nanomolar affinity and single target specificity of the parent 5D3 antibody. Importantly, using a murine xenograft model of PCa, we verified the suitability of fluorescently labeled fragments for in vivo imaging of PSMA-positive tumors and compared their pharmacokinetics and tissue distribution to the parent mAb. Collectively, our data provide an experimental basis for the further development of 5D3 recombinant fragments for future clinical use. Full article

The impact of absorbing aerosols on climate is complex, with their potential positive or negative forcing, depending on many factors, including their height distribution and reflective properties of the underlying background. Measurement data is very limited, due to insufficient remote sensing methods dedicated to the retrieval of their vertical distribution. Columnar values of absorbing aerosol optical depth (AAOD) and single scattering albedo (SSA) are retrieved by the Aerosol Robotic Network (AERONET). However, the number of available results is low due to sky condition and aerosol optical depth (AOD) limitation. Presented research describes results of field campaigns in Strzyżów (South-East Poland, Eastern Europe) dedicated to the comparison of the absorption coefficient and SSA measurements performed with on-ground in-situ devices (aethalomter, nephelometer), small unmanned aerial system (UAS) carrying micro-aethalometer, as well as with lidar/ceilometer. An important aspect is the comparison of measurement results with those delivered by AERONET. Correlation of absorption to scattering coefficients measured on ground (0.79) and correlation of extinction on ground to AOD measured by AERONET (0.77) was visibly higher than correlation between AOD and AAOD retrieved by AERONET (0.56). Columnar SSA was weakly correlated with ground SSA (higher values of columnar SSA), which were mainly explained by hygroscopic effects, increasing scattering coefficient in ambient (wet conditions), and partly high uncertainty of SSA retrieval. AAOD derived with the use of profiles from UAS up to PBL height, was estimated to contribute in average to 37% of the total AAOD. A method of AAOD estimation, in the whole troposphere, with use of measured vertical profiles of absorption coefficient and extinction coefficient profiles from lidars was proposed. AAOD measured with this method has poor correlation with AERONET data, however for some measurements, within PBL, AAOD was higher than reported by AERONET, suggesting potential underestimation in photometric measurement under particular conditions. Correlation of absorption coefficient in profile to on ground measurements decrease with altitude. Measurements of SSA from drones agree well with ground measurements and are lower than results from AERONET, which suggests a larger contribution of absorbing aerosols. As an alternative for AAOD estimation in case of lack of AERONET AAOD data simple models are proposed, which base on AOD scaling with SSA measured with different methods. Proposed solution increase potential of absorption coefficient measurements in vertical profiles and columns of the atmosphere. Presented solutions make measurements of absorption coefficients in vertical profiles more affordable and allow rough estimation of columnar values for the whole atmosphere. Full article