Synthesis of novel coumarin-triazole hybrids and first evaluation of the 4-phenyl substituted hybrid loaded PLGA nanoparticles delivery system to the anticancer activity.

Despite the discovery of many chemotherapeutic drugs that prevent uncontrolled cell division processes in the last century, many studies are still being carried out to develop drugs with higher anticancer efficacy and lower level of side effects. Herein, we designed, synthesized, and characterized six novel coumarin-triazole hybrids, and evaluated for anticancer activity of the one with the highest potential against the breast cancer cell line, MCF-7 and human cervical cancer cell line, human cervical adenocarcinoma (HeLa). Compound21which was the coumarin derivative including phenyl substituent with the lowest IC50 value displayed the highest cytotoxicity against the studied cancer cell line. Furthermore, the potential use of poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) prepared by the emulsifying solvent evaporation method as a platform for a drug delivery system was studied on a selected coumarin derivative21. This coumarin derivative-loaded PLGA NPs were produced with an average size of 225.90 ± 2.96 nm, -16.90 ± 0.85 mV zeta potential, and 4.12 ± 0.90% drug loading capacity. The obtained21-loaded PLGA nanoparticles were analyzed spectroscopically and microscopically with FT-IR, UV-vis, and scanning electron microscopy as well as thermogravimetric analysis, Raman, and x-ray diffraction. Thein vitrorelease of21from the nanoparticles exhibited a controlled release profile just over one month following a burst release in the initial six hours and in addition to this a total release ratio of %50 and %85 were obtained at pH 7.4 and 5.5, respectively.21-loaded PLGA nanoparticles displayed remarkably effective anticancer activity than21. The IC50 values were determined as IC50(21-loaded PLGA nanoparticles): 0.42 ± 0.01 mg ml-1and IC50(free21molecule): 5.74 ± 3.82 mg ml-1against MCF-7 cells, and as IC50(21-loaded PLGA nanoparticles): 0.77 ± 0.12 mg ml-1and IC50(free21molecule): 1.32 ± 0.31 mg ml-1against HeLa cells after the incubation period of 24 h. Our findings indicated that triazole-substituted coumarins may be used as an anticancer agent by integrating them into a polymeric drug delivery system providing improved drug loading and effective controlled drug release.

Host-Guest Interactions of Caffeic Acid Phenethyl Ester with ß-Cyclodextrins: Preparation, Characterization, and In Vitro Antioxidant and Antibacterial Activity.

The aim of this study is to improve the solubility, chemical stability, and in vitro biological activity of caffeic acid phenethyl ester (CAPE) by forming inclusion complexes with ß-cyclodextrin (ß-CD) and hydroxypropyl-ß-cyclodextrin (Hß-CD) using the solvent evaporation method. The CAPE contents of the produced complexes were determined, and the complexes with the highest CAPE contents were selected for further characterization. Detailed characterization of inclusion complexes was performed by using Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and electrospray ionization-mass spectrometry (ESI-MS). pH and thermal stability studies showed that both selected inclusion complexes exhibited better stability compared to free CAPE. Moreover, their antimicrobial activities were evaluated against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) for the first time. According to the broth dilution assay, complexes with the highest CAPE content (10C/ß-CD and 10C/Hß-CD) exhibited considerable growth inhibition effects against both bacteria, 31.25 µg/mL and 62.5 µg/mL, respectively; contrarily, this value for free CAPE was 500 µg/mL. Furthermore, it was determined that the in vitro antioxidant activity of the complexes increased by about two times compared to free CAPE.

Radioligand Therapy With 177 Lu-PSMA-I&T in Patients With Metastatic Prostate Cancer : Oncological Outcomes and Toxicity Profile.

INTRODUCTION: This study aimed to investigate the oncological outcomes and toxicity profile of 177 Lu-PSMA-I&T radioligand therapy (RLT) in patients with metastatic castration-resistant prostate cancer (mCRPC), as well as our initial experience in metastatic hormone-sensitive prostate cancer (mHSPC). PATIENTS AND METHODS: A total of 38 consecutive patients with metastatic prostate cancer (33 mCRPC and 5 mHSPC) received 177 Lu-PSMA-I&T RLT, with a median of 2 cycles per patient (range, 1-7). Response to RLT was evaluated based on prostate-specific antigen (PSA) changes and imaging response. Clinical progression-free survival and overall survival were used to report oncological outcomes. Toxicity was assessed using the Common Toxicity Criteria for Adverse Events criteria. RESULTS: In mCRPC, 22 (69%), 18 (56%), and 11 (34%) patients achieved any PSA decline, PSA response of ≥30%, and PSA response of ≥50%, respectively. The clinical progression-free survival and overall survival after the first cycle of RLT were 6.3 and 21.4 months, respectively. In mHSPC, 177 Lu-PSMA-I&T RLT resulted in excellent PSA response (93.0%-99.9%) in all cases. Clinical progression and cancer-related mortality occurred in only 1 case. Toxicity profile was favorable in both mHSPC and mCRPC. CONCLUSIONS: 177 Lu-PSMA-I&T RLT demonstrated favorable PSA response (≥30%) in over half of the patients with mCRPC and excellent PSA response in all patients with mHSPC. Toxicity profile was favorable in both mHSPC and mCRPC settings. Further studies are needed to evaluate the role of 177 Lu-PSMA-I&T RLT in the management of metastatic prostate cancer.

Agglomerated serum albumin adsorbed protocatechuic acid coated superparamagnetic iron oxide nanoparticles as a theranostic agent.

Iron oxide nanoparticles have been one of the most widely used nanomaterials in biomedical applications. However, the incomplete understanding of the toxicity mechanisms limits their use in diagnosis and treatment processes. Many parameters are associated with their toxicity such as size, surface modification, solubility, concentration and immunogenicity. Further research needs to be done to address toxicity-related concerns and to increase its effectiveness in various applications. Herein, colloidally stable nanoparticles were prepared by coating magnetic iron oxide nanoparticles (MIONPs) with protocatechuic acid (PCA) which served as a stabilizer and a linkage for a further functional layer. A new perfusion agent with magnetic imaging capability was produced by the adsorption of biocompatible passivating agent macro-aggregated albumin (MAA) on the PCA-coated MIONPs. PCA-coated MIONPs were investigated using infrared spectroscopy, thermogravimetric analysis and dynamic light scattering while adsorption of MAA was analysed by transmission electron microscopy, Fourier-transform infrared spectroscopy and x-ray diffraction methods. Magnetic measurements of samples indicated that all samples showed superparamagnetic behaviour. Cytotoxicity results revealed that the adsorption of MAA onto PCA-coated MIONPs provided an advantage by diminishing their toxicity against the L929 mouse fibroblast cell line compared to bare Fe3O4.

Outcomes of antenatally diagnosed fetal cardiac tumors: a 10-year experience at a single tertiary referral center.

OBJECTIVE: The purpose of this study was to analyze the clinical and perinatal outcomes along with ultrasonographic characteristics of fetuses with a cardiac tumor. METHODS: The data were obtained retrospectively between January 2010 and December 2019 in a tertiary referral center. The Cardiovascular Profile Score (CVPS) was used for the diagnosis of heart failure. Clinical outcomes of the cases identified in the postnatal period were analyzed. RESULTS: Fourteen cases were evaluated with the fetal cardiac tumor. One case made the decision to terminate the pregnancy. Perinatal death was seen in 4 (30.7 %) cases out of 13 cases. In 3/14 (21.4%) cases, a solitary cardiac tumor was found while multiple cardiac tumors were found in 11/14 (78.6%) cases. All living cases 9/9 (100%) had the diagnosis of tuberous sclerosis complex (TSC). When the cases which survived were compared with the cases which died during the prenatal period, a significant difference in tumors' biggest diameters (16.44 ± 5.12 mm vs. 32.25 ± 9.28 mm; p: .011, respectively) was found. No statistically significant difference was found in the number of the tumor(s) and heart failure. CONCLUSION: Fetal cardiac tumors can have serious perinatal mortality. The cardiac tumor size was found to be associated with perinatal mortality. The survival is not different between the cases with solitary and multiple tumors and those with and without congestive heart failure.

A nanotechnological approach in the current therapy of COVID-19: model drug oseltamivir-phosphate loaded PLGA nanoparticles targeted with spike protein binder peptide of SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) is today's most serious epidemic disease threatening the human race. The initial therapeutic approach of SARS-CoV-2 disease is based upon the binding the receptor-binding site of the spike protein to the host cell's ACE-2 receptor on the plasma membrane. In this study, it is aimed to develop a biocompatible and biodegradable polymeric drug delivery system that is targeted to the relevant receptor binding site and provides controlled drug release. Oseltamivir phosphate (OP) is an orally administered antiviral prodrug for primary therapy of the disease in biochemically activated carboxylate form (oseltamivir carboxylate OC). In the presented study, model drug OP loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) targeted with spike-binding peptide 1 (SBP1) of SARS-CoV-2 were designed to be used as an efficient and prolonged released antiviral drug delivery system. RY, EE, and DL values of the OP-loaded NPs produced by the solvent evaporation method were calculated to be 59.3%, 61.4%, and 26.9%, respectively. The particle size of OP-loaded NPs and OP-loaded NPs targeted with SBP1 peptide were 162.0 ± 11.0 and 226.9 ± 21.4 nm, respectively. While the zeta potential of the produced OP-loaded NPs was achieved negatively -23.9 ± 1.21 mV), the result of the modification with SBP1 peptide this value approached zero as -4.59 ± 0.728 mV. Morphological features of the OP-loaded NPs were evaluated using FEG-SEM. The further characterization and surface modification of the NPs were analyzed by FT-IR.In-vitrorelease studies of NPs showed that sustained release of OP occurred for two months that fitting the Higuchi kinetic model. By evaluating these outputs, it was reported that surface modification of OP-loaded NPs was significantly effective on characteristics such as size, zeta potential values, surface functionality, and release behavior. The therapeutic model drug-loaded polymeric formulation targeted with a specific peptide may serve as an alternative to more effective and controlled release pharmaceuticals in the treatment of COVID-19 upon an extensive investigation.

Extramedullary Relapsed Multiple Myeloma Treatment With 177Lu-Labeled CXCR4 Endoradiotherapy and Dosimetric Results.

ABSTRACT: We created our first national clinical protocol of 177Lu-CXCR4 therapy for patient who have failed to respond to current therapy options. We also calculated the kidney, liver, and tumor dosimetry. The kidney's mean absorbed dose was calculated to be 0.45 Gy/GBq, the calculated radiation absorbed dose of the liver was 0.63 Gy/GBq, and the radiation absorbed doses of the tumors vary between 9.2 and 82 Gy/GBq. 177Lu-CXCR4 therapy produced a promising clinical response in our patient in acceptable radiation dose limits as a treatment option in heavily pretreated patients with advanced multiple myeloma.

Determination of thyroglobulin levels by radioimmunoassay method in anti thyroglobulin positive differentiated thyroid patients: One center clinical experience.

It is very crucial to determine Tg accurately and precisely in thyroid cancer cases. Although there are many studies on the detection of Tg in thyroid cases in the literature, there are no sufficient clinical studies examining many cases with different features by using RIA methodology. Here, a radiometric and chromatographic method has been studied for the first time to eliminate the interference from anti-Tg positive patients. In this paper, radioimmunoassay (RIA) and immunoradiometric (IRMA) techniques were used for the analysis of 302 sera collected from patients for Tg and TgAb quantification. By the RIA technique, a reliable result was obtained by calculating the real Tg value quantitatively in 41 patients showing TgAb positivity out of 208 patients. Our findings show that the RIA assay is the most suitable approach for detection of changeable (low or undetectable) Tg value and metastases detected by post-therapeutic imaging in early-stage DTC cases showing preoperative and postoperative TgAb positivity. The new immunoradiometric method allows the real (%) Tg value to be reached in a part of TgAb-positive DTC. Even if TgAb positive in the metastatic and nonmetastatic DTC patient group. This allows the accurate clinical follow-up of patients.

An insight into the epitope-based peptide vaccine design strategy and studies against COVID-19.

SARS-CoV-2 is a new member of the coronavirus family and caused the pandemic of coronavirus disease 2019 (COVID-19) in 2020. It is crucial to design and produce an effective vaccine for the prevention of rapid transmission and possible deaths wcaused by the disease. Although intensive work and research are being carried out all over the world to develop a vaccine, an effective and approved formulation that can prevent the infection and limit the outbreak has not been announced yet. Among all types of vaccines, epitope-based peptide vaccines outshine with their low-cost production, easy modification in the structure, and safety. In this review, vaccine studies against COVID-19 have been summarized and detailed information about the epitope-based peptide vaccines against COVID-19 has been provided. We have not only compared the peptide vaccine with other types of vaccines but also presented comprehensive literature information about development steps for an effective and protective formulation to give an insight into on-going peptide vaccine studies against SARS-CoV-2.

Posttherapeutic Critical Organ Dosimetry of Extensive 177Lu-PSMA Inhibitor Therapy With Metastatic Castration-Resistant Prostate Cancer: One Center Results.

PURPOSE: Lu-PSMA inhibitor peptide receptor radioligand therapy (RLT) is playing an increasing role in metastatic castration-resistant prostate cancer. We aimed to estimate the absorbed radiation doses for critical organs (eg, kidneys, parotid glands, submandibular glands, and lacrimal glands) of patients treated with 4 to 6 cycles by Lu-PSMA inhibitor RLT, retrospectively, and to evaluate the findings extensively in order to determine the critical organ radiation-absorbed limitations and the number of prospective RLT. MATERIALS AND METHODS: A total of 51 cycles Lu-PSMA inhibitor RLT in 10 patients was analyzed. Therapies have been applied in 4 to 6 cycles with 8 to 10 weeks' intervals. Dosimetric estimates of kidneys, parotid glands, submandibular glands, and lacrimal glands have been calculated based on MIRD scheme pamphlet no. 16. Regions of interest were drawn with GE Xeleris Functional Imaging Workstation. OLINDA/EXM 1.1 simulation software was used to calculate radiation-absorbed doses. RESULTS: Mean radiation-absorbed doses were 0.70 ± 0.24 Gy/GBq for kidneys, 1.34 ± 0.78 Gy/GBq for parotid glands, 0.94 ± 0.45 Gy/GBq for submandibular glands, and 2.28 ± 1.29 Gy/GBq for lacrimal glands. CONCLUSIONS: Due to the critical target organ risks and the optimal therapy doses, patient-specific dosimetry is a deterministic factor in radionuclide therapy. Even when the absorbed kidney doses were above the ICRP critical dose limits in patients who had 4 to 6 cycles of therapy, mortality due to nephrotoxicity has not been observed. Mild increased tolerated radiation dose is acceptable for the patient groups with very low survival rate.

Synthesis and characterization of natural lanthanum labelled DOTA-Peptides for simulating radioactive Ac-225 labeling.

This research aimed to assess the labeling procedure of Lanthanum to DOTATATE and PSMA-617 peptide for simulating Actinium-225 (225Ac) labeling. For this purpose labeling procedure, purification and characterization conditions were optimized. Results showed that for the high reaction yield labeling, microwave heating should be preferred and Sephadex G10 column was found to be more suitable as a purification system compared to Toyopearl column. For the characterization of complex, more precise and reliable results were obtained by the chromatographic system.

The Utility of 68Ga-PSMA PET/CT in Poorly Differentiated Metastatic Prostate Cancer.

We aimed to emphasize how useful PSMA PET/CT findings can be while trying to restage prostate cancer after radical prostatectomy in the presence of low prostate-specific antigen values. A 64-year-old man with pT3b N1 M0 Gleason 7 adenocarcinoma of the prostate presented 5 years postoperatively with a palpable axillary mass, whereas his prostate-specific antigen was 0.08 ng/mL. Conventional imaging studies and histopathologic findings of the axillary mass biopsy revealed inconclusive results. Ga-PSMA PET/CT demonstrated PSMA-positive metastatic lesions, the largest one being located in the right axilla. This finding confirmed metastatic poorly differentiated prostate cancer, and androgen deprivation therapy was initiated.

Prostate-specific membrane antigen-based imaging in prostate cancer: impact on clinical decision making process.

BACKGROUND: There is an ongoing need for an accurate imaging modality which can be used for staging purposes, metastatic evaluation, predicting biologic aggresiveness and investigating recurrent disease in prostate cancer. Prostate specific membrane antigen, given its favorable molecular characteristics, holds a promise as an ideal target for prostate cancer-specific nuclear imaging. In this study, we evaluated our initial results of PSMA based PET/CT imaging in prostate cancer. METHODS: A total of 22 patients with a median age and serum PSA level of 68 years and 4.15 ng/ml, respectively underwent Ga-68 PSMA PET/CT in our hospital between Februrary and August 2014. Their charts were retrospectively reviewed in order to document the clinical characteristics, the indications for and the results of PSMA based imaging and the impact of Ga-68 PSMA PET/CT findings on disease management. RESULTS: The most common indications were rising PSA after local ± adjuvant treatment followed by staging and metastatic evaluation before definitive or salvage treatment. All except 2 patients had prostatic ± extraprostatic PSMA positive lesions. For those who had a positive result; treatment strategies were tailored accordingly. Above the PSA level of 2 ng/ml, none of the PSMA based nuclear imaging studies revealed negative results. CONCLUSIONS: PSMA based nuclear imaging has significantly impacted our way of handling patients with prostate cancer. Its preliminary performance in different clinical scenarios and ability to detect lesions even in low PSA values seems fairly promising and deserves to be supplemented with further clinical studies.