ABSTRACT
Rapid identification of drug mechanisms is vital to the development and effective use of chemotherapeutics. Herein, we develop a multichannel surface-enhanced Raman scattering (SERS) sensor array and apply deep learning approaches to realize the rapid identification of the mechanisms of various chemotherapeutic drugs. By implementing a series of self-assembled monolayers (SAMs) with varied molecular characteristics to promote heterogeneous physicochemical interactions at the interfaces, the sensor can generate diversified SERS signatures for directly high-dimensionality fingerprinting drug-induced molecular changes in cells. We further train the convolutional neural network model on the multidimensional SAM-modulated SERS data set and achieve a discriminatory accuracy toward 99%. We expect that such a platform will contribute to expanding the toolbox for drug screening and characterization and facilitate the drug development process.
Subject(s)
Deep Learning , Spectrum Analysis, Raman , Spectrum Analysis, Raman/methods , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/analysis , Surface PropertiesABSTRACT
BACKGROUND: The unique size, physical and chemical properties, and ultra-high stability of nanozymes have attracted extensive attentions in sensing, but improvement of catalytic activity of the nanozymes is still an urgent issue. Given the ultra-high simulated enzyme activity of metal nanoparticles and the advantage of multi-enzyme catalysis, an Au-decorated MoS2 nanosheets (MoS2/Au NS) integrating the double peroxidase-like (POD) activity is developed. RESULTS: By optimizing and adjusting the density of AuNPs, as well as its morphology and other parameters, a monodisperse and high-density distribution of AuNPs on MoS2 nanosheets was obtained, which can greatly improve the POD-like activity of MoS2/Au NS. Nafion solution was applied to assist the modification of MoS2/Au NS on the electrode surface so as to improved its stability. An electrochemical H2O2 detection platform was constructed by modifying MoS2/Au NS nanozyme on the SPCE using the conductive Nafion solution. And the negatively charged sulfonic acid group can eliminate negatively charged electroactive substances to improve the specificity. Then ascorbic acid was used to stimulate tumor cells to produce H2O2 as therapeutic model, an ultrasensitive chronocoulometry detection for H2O2 in cell lysate was established. The logarithmically of ΔQ and the logarithmically of H2O2 concentration showed a good linear relationship between 1 µM and 500 mM, with a LOD value of 0.3 µM. SIGNIFICANCE: The developed H2O2 sensor has excellent stability, reproducibility (RSD = 2.3 %, n = 6) and selectivity, realized the quantitative detection of H2O2 in cell lysate. Compared with commercial fluorescence detection kits for H2O2 in cell lysate, it is worth mentioning that the electrochemical H2O2 sensor developed in this study is simpler and faster, with higher sensitivity and lower cost. This provides a potential substitute for disease diagnosis and treatment evaluation based on accurate detection of H2O2.
Subject(s)
Antineoplastic Agents , Disulfides , Electrochemical Techniques , Gold , Hydrogen Peroxide , Metal Nanoparticles , Molybdenum , Gold/chemistry , Molybdenum/chemistry , Hydrogen Peroxide/analysis , Hydrogen Peroxide/chemistry , Disulfides/chemistry , Metal Nanoparticles/chemistry , Electrochemical Techniques/methods , Humans , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/analysis , Nanostructures/chemistry , Limit of Detection , Peroxidase/chemistry , Peroxidase/metabolism , Drug Screening Assays, AntitumorABSTRACT
Cancer remains one of the leading causes for death worldwide. Palliative chemotherapy is vital for certain cancer patients, highlighting the critical need for treatment monitoring tools to prevent drug accumulation and mitigate the risk of high toxicity. Therefore, our aim was to evaluate the potential of screen-printed electrodes for the development of sensitive and accurate biosensors for the detection/quantification of antineoplastic drugs. To this purpose, we developed a cisplatin sensor. By functionalizing the gold electrode with human serum albumin and by collecting the electrochemical signal obtained in a H2O2 solution, through voltammetry measurements, we were able to correlate the current measured at 430 mV with the concentration of cisplatin present in human serum samples, with a correlation coefficient of R2 = 0.99. Also, a bleomycin biosensor was developed and proven functional, but further optimization steps were employed in order to improve the accuracy. The developed biosensors have a detection range of 0.0006-43.2 mg/mL for cisplatin and 0.23-7.56 µg/mL for bleomycin in the serum samples. Our preliminary results show that these biosensors can facilitate the real-time monitoring of cisplatin and bleomycin serum levels, allowing healthcare professionals to tailor treatment strategies based on individual patient responses.
Subject(s)
Antineoplastic Agents , Biosensing Techniques , Bleomycin , Cisplatin , Electrodes , Bleomycin/blood , Cisplatin/blood , Humans , Biosensing Techniques/methods , Antineoplastic Agents/blood , Antineoplastic Agents/analysis , Serum Albumin, Human/analysis , Electrochemical Techniques/methods , Gold/chemistryABSTRACT
Palbociclib (Ibrance; Pfizer) was approved for the management of metastatic breast cancer characterized by hormone receptor-positive/human epidermal growth factor receptor 2 negative status. The objective of this study was to create a fast, precise, environmentally friendly, and highly sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry approach for quantifying palbociclib (PAB) in human liver microsomes with the application for assessing metabolic stability. The validation features were performed in agreement with the bioanalytical method validation standards outlined by the US Food and Drug Administration. The StarDrop software (WhichP450 and DEREK modules) was used in screening the metabolic lability and structural alerts of PAB. The separation of PAB and encorafenib (as an internal standard) was achieved on a C8 column, employing an isocratic mobile phase. The inter-day and intra-day accuracy and precision ranged from -6.00% to 4.64% and from -2.33% to 3.13%, respectively. The constructed calibration curve displayed a linearity in the range of 1-3000 ng/mL. The sensitivity of the established approach was proven by the lower limit of quantification of 0.73 ng/mL. The Analytical GREEness calculator results revealed the high level of greenness of the developed method. The PAB's metabolic stability (t1/2 of 18.5 min and a moderate clearance (Clint) of 44.8 mL/min/kg) suggests a high extraction ratio medication that matched the WhichP450 software results.
Subject(s)
Microsomes, Liver , Piperazines , Pyridines , Tandem Mass Spectrometry , Humans , Piperazines/metabolism , Piperazines/analysis , Piperazines/chemistry , Microsomes, Liver/metabolism , Microsomes, Liver/chemistry , Pyridines/metabolism , Pyridines/chemistry , Pyridines/analysis , Chromatography, High Pressure Liquid , Computer Simulation , Antineoplastic Agents/analysis , Antineoplastic Agents/metabolism , Antineoplastic Agents/chemistryABSTRACT
Interest is increasing in the use of different liquid chromatography techniques coupled online to mass spectrometry for the quantification of platinum anticancer drugs in human plasma to inform cancer chemotherapy. We developed, validated and studied the application of a method for quantification of intact oxaliplatin in human plasma using ultra high performance liquid chromatography hyphenated to inductively coupled plasma mass spectrometry (UHPLC-ICP-MS). Plasma samples were processed instantly after collection from patients to preserve oxaliplatin speciation by methanol-deproteinization, and storage of diluted supernatants (plasma:methanol 1:2 v/v) at -80 °C. UHPLC separation of intact oxaliplatin and internal standard (carboplatin) was achieved using a C18 column and linear gradient mobile phase (Mobile phase A: water-methanol (97:3 v/v), 0.075 mM sodium dodecyl sulfate, 9.79 nM thallium adjusted to pH 2.5 with trifluoromethanesulfonic acid; Mobile phase B: 100 % methanol (v/v)) with ICP-MS detection to monitor platinum and thallium at m/z 195 and 205, respectively. The limit of quantification was 50 nM in methanol-deproteinized diluted plasma (1:2 v/v). Linearity was established for calibration standards ranging from 50 to 500 nM made in methanol-deproteinized diluted plasma (1:2 v/v), and for dilution of higher concentration samples in blank matrix containing internal standard (final dilution 1:29 v/v). Intra-day and inter-day accuracy ranged from 96.8 to 103 % of nominal concentration and precision from 0.62 to 2.49 % coefficient of variation. Recovery was complete and a matrix effect confirmed the requirement for matrix-matched standards. Intact oxaliplatin was stable during storage for at least 473 days, and during analysis, in methanol-deproteinized diluted plasma (1:2 v/v). The method was applied to determining the plasma concentrations of intact oxaliplatin in patients undergoing cancer chemotherapy, and studies of oxaliplatin degradation in vitro. This improved method based on UHPLC-ICP-MS will allow more specific, efficient and reliable quantification of intact oxaliplatin in human plasma.
Subject(s)
Limit of Detection , Mass Spectrometry , Oxaliplatin , Humans , Oxaliplatin/blood , Oxaliplatin/chemistry , Chromatography, High Pressure Liquid/methods , Mass Spectrometry/methods , Reproducibility of Results , Antineoplastic Agents/blood , Antineoplastic Agents/chemistry , Antineoplastic Agents/analysis , Linear Models , Organoplatinum Compounds/blood , Organoplatinum Compounds/chemistryABSTRACT
Dimethyl 2-[2-(1-phenyl-4,5-dihydro-1H-imidazol-2-yl)hydrazinylidene]butanedioate (DIHB) and 8-(3-chlorophenyl)-2,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazine-3,4-dione (HDIT) are promising candidates for anticancer agents, the first analytical procedures of which are presented in this paper. The commercially available unmodified glassy carbon electrode (GCE) was used as a sensor for the individual and simultaneous differential pulse voltammetric (DPV) determination of these possible anticancer drugs. The findings concerning the electrochemical behaviour indicated that DIHB and HDIT display at GCE, as a sensor, the oxidation peaks at 1.18 and 0.98 V, respectively (vs. Ag/AgCl, 3.0 mol L-1 KCl) in the 0.125 mol L-1 acetate buffer of pH = 4.5, which were employed for their quantification. Various experimental parameters were carefully investigated, to achieve high sensitivity in voltammetric measurements. Finally, under the optimised conditions (t of 60 s, ΔEA of 75 mV, ν of 225 mV s-1, and tm of 2 ms), the proposed DPV procedure with the GCE demonstrated broad linear sensing ranges (1-200 nmol L-1-DIHB and 5-200 nmol L-1-HDIT), boasting the detection limits of 0.18 nmol L-1 for DIHB and 1.1 nmol L-1 for HDIT. Moreover, the developed procedure was distinguished by good selectivity, repeatability of DIHB and HDIT signals and sensor reproducibility. The practical application of this method was demonstrated by analysing the urine reference material without any prior treatment. The results showed that this environmentally friendly approach, with a modification-free sensor, is suitable for the sensitive, selective and rapid quantification of DIHB and HDIT.
Subject(s)
Antineoplastic Agents , Carbon , Electrochemical Techniques , Electrodes , Antineoplastic Agents/analysis , Carbon/chemistry , Humans , Electrochemical Techniques/methods , Limit of Detection , Oxidation-ReductionABSTRACT
A novel and robust electrochemical sensing tool for the determination of vismodegib (VIS), an anticancer drug, has been developed by integrating the selective recognition capabilities of molecularly imprinted polymer (MIP) and the sensitivity enhancement capability of metal-organic framework (MOF). Prior to this step, the electrochemical behavior of VIS was investigated using a bare glassy carbon electrode (GCE). It was observed that in 0.5 M H2SO4 solution as electrolyte, VIS has an oxidation peak around 1.3 V and the oxidation mechanism is diffusion controlled. The determination of VIS in a standard solution using a bare GCE showed a linear response in the concentration range from 2.5 µM to 100 µM, with a limit of detection (LOD) of 0.75 µM. Since sufficient sensitivity and selectivity could not be achieved with bare GCE, a MIP sensor was developed in the next step of the study. For this purpose, the GCE surface was first modified by drop casting with as-synthesized Co-MOF. Subsequently, a MIP network was synthesized via a thermal polymerization approach using 2-acrylamido-2-methylpropanesulfonic acid (AMPS) as monomer and VIS as template. MOFs are ideal electrode materials due to their controllable and diverse morphologies and modifiable surface properties. These characteristics enable the development of MIPs with more homogeneous binding sites and high affinity for target molecules. Integrating MOFs could help the performance of sensors with the desired stability and reproducibility. Electrochemical analysis revealed an observable enhancement of the output signal by the incorporation of MOF molecules, which is consistent with the sensitivity-enhancing role of MOF by providing more anchoring sites for the attachment of the polymer texture to the electrode surface. This MOF-MIP sensor exhibited impressive linear dynamic ranges ranging from 0.1 to 1.0 pM for VIS, with detection limits in the low picomolar range. In addition, the MOF-MIP sensor offers high accuracy, selectivity and precision for the determination of VIS, with no interference observed from complex media of serum samples. Additionally, in this study, Analytical GREEnness metric (AGREE), Analytical GREEnness preparation (AGREEprep) and Blue Applicability Grade Index (BAGI) were used to calculate the green profile score.
Subject(s)
Anilides , Antineoplastic Agents , Electrochemical Techniques , Electrodes , Metal-Organic Frameworks , Molecularly Imprinted Polymers , Pyridines , Metal-Organic Frameworks/chemistry , Molecularly Imprinted Polymers/chemistry , Pyridines/chemistry , Electrochemical Techniques/methods , Antineoplastic Agents/analysis , Antineoplastic Agents/chemistry , Antineoplastic Agents/blood , Anilides/chemistry , Anilides/analysis , Anilides/blood , Limit of Detection , Molecular Imprinting , Polymers/chemistryABSTRACT
In our research we explore the world of PACDs, carbon dots synthesized from pamoic acid through a single step pyrolysis method. Our findings reveal that PACDs have capabilities of serving as sensitive and selective sensors in both colorimetric and fluorescent modes. They are particularly effective, at colorimetrically and fluorometrically detecting ferric ions and can also act as fluorometric sensors for pH. When ferric ions are introduced an interesting transformation occurs. A noticeable change in color unfolds before our eyes, under 365 nm UV light the fluorescence shifts from green to blue while in daylight it changes from a yellow to a deep ink blue. Notably these detection techniques can precisely measure ferric ions within concentrations ranging from 5 µM to 80 µM with a detection limit of 0.1 µM for fluorescence response. Additionally, they can detect ferric ions colorimetrically within the range of 5 µM to 45 µM with a detection limit of 3.8 µM. Furthermore, the PACDs exhibit a capability to adapt to different pH levels. In alkaline environments with a pH range between 8 and 11 the fluorescence signal demonstrates a response that directly correlates with pH levels and slightly shifts its position. In contrast under acidic conditions a noticeable shift, towards blue is observed in the fluorescence signal leading to a change in color from green to blue when exposed to UV light. This shift persists as the fluorescence signal directly correlates with decreasing pH levels in settings. Apart from their proficiency in ferric ion detection and pH monitoring, the PACDs also demonstrate potential in cancer research. Through an assessment using the MTT assay it was discovered that the PACDs exhibit cytotoxic effects against five different cancer cell lines; HCT 116, MDA MB 231, Hep3B, MCF 7 and HeLa. The findings are promising as the PACDs show IC50 values of 12.5 µg/ml 6.25 µg/ml 25 µg/ml 50 µg/ml and 100 µg/ml for these cell lines. This research highlights the versatility and potential of PACDs as a tool, in both sensing applications and oncology research.
Subject(s)
Carbon , Quantum Dots , Spectrometry, Fluorescence , Humans , Carbon/chemistry , Quantum Dots/chemistry , Hydrogen-Ion Concentration , Colorimetry/methods , Limit of Detection , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/analysisABSTRACT
A novel electrochemical sensor based on LaNiO3/g-C3N4@RGH nanocomposite material was developed to simultaneously determine Ribociclib (RIBO) and Alpelisib (ALPE). Ribociclib and Alpelisib are vital anticancer medications used in the treatment of advanced breast cancer. The sensor exhibited excellent electrocatalytic activity towards the oxidation of RIBO and ALPE, enabling their simultaneous detection. The fabricated sensor was characterized using various techniques, including energy dispersive X-ray (EDX), Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction (XR), scanning electron microscopy (SEM), and X-ray photoelectron spectroscopy (XPS), which confirmed the successful synthesis of the LaNiO3/g-C3N4@RGH composite material. Electrochemical characterization revealed enhanced conductivity and lower resistance of the modified electrode compared to the bare electrode. The developed sensor exhibited high repeatability, reproducibility, stability, and selectivity toward RIBO detection. Furthermore, the sensor displayed high sensitivity with low detection limits of 0.88 nM for RIBO and 6.1 nM for ALPE, and linear ranges of 0.05-6.2 µM and 0.5-6.5 µM, respectively. The proposed electrochemical sensor offers a promising approach for simultaneously determining RIBO and ALPE in pharmaceutical formulations and biological samples with recovery data of 98.7-102.0 %, providing a valuable tool for anticancer drug analysis and clinical research.
Subject(s)
Antineoplastic Agents , Electrochemical Techniques , Nanocomposites , Nanocomposites/chemistry , Antineoplastic Agents/analysis , Antineoplastic Agents/chemistry , Electrochemical Techniques/methods , Electrodes , Humans , Graphite/chemistry , Limit of DetectionABSTRACT
In this work, UiO-66-NH2/GO nanocomposite was prepared using a simple solvothermal technique, and its structure and morphology were characterized using field emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy (EDS), and X-ray diffraction (XRD). An enhanced electrochemical sensor for the detection of epirubicin (EP) was proposed, which utilized a UiO-66-NH2/GO nanocomposite-modified screen-printed graphite electrode (UiO-66-NH2/GO/SPGE). The prepared UiO-66-NH2/GO nanocomposite improved the electrochemical performance of the SPGE towards the redox reaction of EP. Under optimized experimental conditions, this sensor demonstrates a remarkable limit of detection (LOD) of 0.003 µM and a linear dynamic range from 0.008 to 200.0 µM, providing a highly capable platform for sensing EP. Furthermore, the simultaneous electro-catalytic oxidation of EP and topotecan (TP) was investigated at the UiO-66-NH2/GO/SPGE surface utilizing differential pulse voltammetry (DPV). DPV measurements revealed the presence of two distinct oxidation peaks of EP and TP, with a peak potential separation of 200 mV. Finally, the UiO-66-NH2/GO/SPGE sensor was successfully utilized for the quantitative analysis of EP and TP in pharmaceutical injection, yielding highly satisfactory results.
Subject(s)
Antineoplastic Agents , Electrochemical Techniques , Electrodes , Epirubicin , Graphite , Nanocomposites , Topotecan , Epirubicin/analysis , Topotecan/analysis , Graphite/chemistry , Antineoplastic Agents/analysis , Biosensing Techniques , Metal-Organic Frameworks/chemistry , Limit of Detection , Humans , Oxidation-Reduction , Phthalic AcidsABSTRACT
Therapeutic drug monitoring (TDM) serves as a potent tool for adjusting drug concentration within a reasonable range. However, continuous monitoring of anticancer drugs in-vivo presents a significant challenge. Herein, we propose a needle-in-needle electrochemical sensor based on an acupuncture needle electrode, capable of monitoring the anticancer drug etoposide in the peritoneal cavity of living rats. The acupuncture needle was modified with Au nanoparticles and etoposide-templated molecularly imprinted polymer (MIP), resulting in high sensitivity and selectivity in the electrochemical detection of etoposide. The modified acupuncture needle (0.16 mm diameter) was anchored inside a syringe needle (1.40 mm diameter), allowing the outer syringe needle to protect the modified materials of the inner acupuncture needle during skin piercing. Due to the unique needle-in-needle design, high stability was obtained during in-vivo etoposide monitoring. Connecting to a smartphone-controlled portable electrochemical workstation, the needle-in-needle sensor offers great convenience in point-of-care TDM. Moreover, the electrode materials on the acupuncture needle were carefully characterized and optimized. Under the optimized conditions, low detection limits and wide linear range were achieved. This work provides new insights into acupuncture needle electrochemical sensors and further expands the feasibility for real-time and in-vivo detection.
Subject(s)
Biosensing Techniques , Drug Monitoring , Etoposide , Gold , Needles , Etoposide/analysis , Etoposide/administration & dosage , Animals , Rats , Biosensing Techniques/instrumentation , Gold/chemistry , Drug Monitoring/instrumentation , Electrochemical Techniques/methods , Antineoplastic Agents/analysis , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/blood , Metal Nanoparticles/chemistry , Molecularly Imprinted Polymers/chemistry , Limit of Detection , Electrodes , Rats, Sprague-Dawley , Equipment DesignABSTRACT
Letrozole is an anticancer medication prescribed for the management of estrogen receptor-positive breast cancer in postmenopausal women. Chronic pain is prevalent in patients receiving chemotherapy, leading to the use of adjuvant analgesics such as tramadol. This work introduces the first analytical approach for the concurrent quantification of letrozole and tramadol, two co-administered drugs, employing a rapid, highly sensitive, eco-friendly, and cost-effective first derivative synchronous spectrofluorimetric technique. The fluorescence of tramadol and letrozole was measured at wavelengths of 235.9 nm and 241.9 nm, respectively using a wavelength difference (Δλ) of 60.0 nm. The developed approach demonstrated exceptional linearity (r Ë 0.999) within the specified concentration ranges for tramadol (10.0-1200.0 ng/mL) and letrozole (1.0-140.0 ng/mL). The results demonstrated that the proposed technique exhibits a high level of sensitivity, with detection limits of 0.569 and 0.143 ng/mL for tramadol and letrozole, respectively, indicating the good bioanalytical applicability. The within-run precisions, both intra-day and inter-day, for both analytes, were less than 0.71 % RSD. The developed approach was effectively applied to simultaneously estimate the mentioned drugs in their tablets and human plasma samples, achieving high percentage recoveries and low % RSD values. In order to assess the environmental sustainability of the developed approach, Analytical GREEnnessNNESS (AGREE) and the Green Analytical Procedure Index (GAPI) metric tools were employed. Both tools revealed that the developed approach is excellent green, suggesting its usage as an environmentally-friendly alternative for the routine assayof the investigated pharmaceuticals. The developed approach was validated according to the ICHQ2 (R1) requirements.
Subject(s)
Breast Neoplasms , Letrozole , Limit of Detection , Spectrometry, Fluorescence , Tramadol , Letrozole/blood , Letrozole/analysis , Letrozole/administration & dosage , Tramadol/blood , Tramadol/analysis , Humans , Spectrometry, Fluorescence/methods , Breast Neoplasms/drug therapy , Breast Neoplasms/blood , Female , Antineoplastic Agents/blood , Antineoplastic Agents/analysis , Reproducibility of Results , TabletsABSTRACT
The main focus of anticancer drug discovery is on developing medications that are gentle on normal cells and should have the ability to target multiple anti-cancer pathways. Liver cancer is becoming a worldwide epidemic due to the highest occurring and reoccurring rate in some countries. Calotropis procera is a xerophytic herbal plant growing wildly in Saudi Arabia. Due to its anti-angiogenic and anticancer capabilities, "C. procera" is a viable option for developing innovative anticancer medicines. However, no study has been done previously, to discover angiogenic and anti-cancer targets which are regulated by C. procera in liver cancer. In this study, leaves, stems, flowers, and seeds of C. procera were used to prepare crude extracts and were fractionated into four solvents of diverse polarities. These bioactivity-guided solvent fractions helped to identify useful compounds with minimal side effects. The phytoconstituents present in the leaves and stem were identified by GC-MS. In silico studies were done to predict the anti-cancer targets by major bioactive constituents present in leaves and stem extracts. A human angiogenesis antibody array was performed to profile novel angiogenic targets. The results from this study showed that C. procera extracts are an ideal anti-cancer remedy with minimum toxicity to normal cells as revealed by zebrafish in vivo toxicity screening assays. The novel antiangiogenic and anticancer targets identified in this study could be explored to design medication against liver cancer.
Subject(s)
Calotropis , Liver Neoplasms , Plant Extracts , Zebrafish , Calotropis/chemistry , Humans , Plant Extracts/pharmacology , Plant Extracts/chemistry , Liver Neoplasms/drug therapy , Animals , Cell Line, Tumor , Breast Neoplasms/drug therapy , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Plant Leaves/chemistry , Female , Angiogenesis Inhibitors/pharmacology , Angiogenesis Inhibitors/chemistry , Computer Simulation , Phytochemicals/pharmacology , Phytochemicals/chemistry , Phytochemicals/analysis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/analysisABSTRACT
The European Medicines Agency (EMA) mandates Environmental Risk Assessments (ERAs) since 2006 to determine potential risks of new marketed medicines. Drugs with a Predicted Environmental Concentration (PEC) in inland surface waters exceeding 0.01 µg L-1 require further environmental risk assessment. PEC may be refined based on prevalence data and/or based on the treatment regimen. In this study, based on EMA regulations, refined PEC of 108 antineoplastic drugs in coastal waters were determined based on the consumption in a coastal health area during 2021, identifying six drugs with potential environmental risk in surface waters (hydroxyurea, capecitabine, abiraterone, ibrutinib, imatinib and 5-fluorouracil) and two in marine ecosystem (hydroxyurea and capecitabine). Comparison of these refined PECs with data from marketing laboratories revealed significant disparities, suggesting the need for regular updates, especially with changes in drug indications or financing. Notably, the identified drugs are not yet on the main reference lists of emerging contaminants.
Subject(s)
Antineoplastic Agents , Environmental Monitoring , Water Pollutants, Chemical , Spain , Water Pollutants, Chemical/analysis , Antineoplastic Agents/analysis , Risk Assessment , EcosystemABSTRACT
BACKGROUND: Estimation of the drug and development of the method is a critical aspect of formulation development and a critical factor for analytical scientists. Gefitinib is a poorly soluble anticancer drug. OBJECTIVE: The present research focuses on the topic of the development of innovative quality by design methods for the estimation of gefitinib (GF) from bulk, pharmaceutical tablet formulation, and complex nanoformulations. METHODS: To simplify the estimation of poorly soluble drugs such as GF, response surface methodology (RSM) was adopted with effective leverages to obtain precise computation design space using the Box-Behnken design (BBD) model. The major three mixed-effect independent factors (percentage of buffer, pH of buffer, and flow rate) were screened with three prominent dependent responses (viz., theoretical plate, retention time, and tailing factor) selected for optimal analysis. Furthermore, co-processed steps were employed for the estimation of the analyte from the complex formulation. RESULTS: The RP-HPLC method uses the quality by design (QbD) approach can effectively estimate the analyte concentration of less than 4.5 min. The developed method was economically robust and sensitive and shows a relative standard deviation (RSD, %) of less than 2% for all the selected validation parameters. The estimated design space suggests the highest desirability (R2-0.998) at 60% of buffer in the mobile phase, pH 4.25, and flow rate of 0.7 mL/min. CONCLUSIONS: The QbD approach was used to design and develop the method by understanding the interaction between dependent and independent variables to get the optimum values. The developed method was validated successfully and can be useful for formulation scientists to estimate drug concentration and drug release profiles from complex nanoformulations. HIGHLIGHTS: The analytical approach was designed and quantified using a quality-by-design approach to make the RP-HPLC method more robust and efficient for the estimation of analytes from complex nanoformulations. The method is also useful to eliminate the interfering molecule during estimation by employing co-processing steps. The developed method saves time and cost of solvent and employs QbD as a requirement of recent regulatory concern.
Subject(s)
Gefitinib , Tablets , Chromatography, High Pressure Liquid/methods , Gefitinib/analysis , Gefitinib/chemistry , Antineoplastic Agents/analysis , Antineoplastic Agents/chemistry , Nanoparticles/chemistry , Drug Compounding/methods , Hydrogen-Ion Concentration , Chromatography, Reverse-Phase/methodsABSTRACT
Healthcare workers handling antineoplastic drugs (ADs) in preparation units run the risk of occupational exposure to contaminated surfaces and associated mutagenic, teratogenic, and oncogenic effects of those drugs. To minimise this risk, automated compounding systems, mainly robots, have been replacing manual preparation of intravenous drugs for the last 20 years now, and their number is on the rise. To evaluate contamination risk and the quality of the working environment for healthcare workers preparing ADs, we applied the Failure Mode Effects and Criticality Analysis (FMECA) method to compare the acceptable risk level (ARL), based on the risk priority number (RPN) calculated from five identified failure modes, with the measured risk level (MRL). The model has shown higher risk of exposure with powdered ADs and containers not protected by external plastic shrink film, but we found no clear difference in contamination risk between manual and automated preparation. This approach could be useful to assess and prevent the risk of occupational exposure for healthcare workers coming from residual cytotoxic contamination both for current handling procedures and the newly designed ones. At the same time, contamination monitoring data can be used to keep track of the quality of working conditions by comparing the observed risk profiles with the proposed ARL. Our study has shown that automated preparation may have an upper hand in terms of safety but still leaves room for improvement, at least in our four hospitals.
Subject(s)
Antineoplastic Agents , Occupational Exposure , Humans , Health Care Sector , Antineoplastic Agents/analysis , Occupational Exposure/adverse effects , Occupational Exposure/prevention & control , Occupational Exposure/analysis , Hospitals , Health Personnel , Environmental Monitoring/methodsABSTRACT
Cnidii Fructus, derived from the dried ripe fruit of Cnidium monnieri (L.) Cuss, has the effect of warming kidneys and invigorating Yang. This study established the spectrum-effect relationships between ultra-high-performance liquid chromatography (UHPLC) fingerprints and the antitumor activities of Cnidii Fructus on human hepatocellular carcinoma (HepG2) cells. In UHPLC fingerprints, 19 common peaks were obtained, and 17 batches of herbs had similarity >0.948. In Cell Counting Kit-8 (CCK-8) test, 17 batches of Cnidii Fructus extract significantly inhibited the proliferation of HepG2 cells to different degrees, showing different half-maximal inhibitory concentration (IC50) values. Furthermore, gray correlation analysis, Pearson's analysis, and orthogonal partial least squares discriminant analysis were performed to screen out eight components. The analysis of mass spectrum data and a comparison with standards revealed that the eight components were methoxsalen, isopimpinellin, osthenol, imperatorin, osthole, ricinoleic acid, linoleic acid, and oleic acid. The verification experiments by testing single compounds indicated that these eight compounds were the major anti-hepatoma compounds in Cnidii Fructus. This work provides a model combining UHPLC fingerprints and antitumor activities to study the spectrum-effect relationships of Cnidii Fructus, which can be used to determine the principal components responsible for the bioactivity.
Subject(s)
Cell Proliferation , Cnidium , Chromatography, High Pressure Liquid/methods , Humans , Hep G2 Cells , Cell Proliferation/drug effects , Cnidium/chemistry , Fruit/chemistry , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/chemistry , Liver Neoplasms/drug therapy , Carcinoma, Hepatocellular/drug therapy , Plant Extracts/pharmacology , Plant Extracts/chemistry , Reproducibility of Results , Antineoplastic Agents, Phytogenic/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/analysis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/analysis , Furocoumarins/pharmacology , Furocoumarins/analysis , Furocoumarins/chemistryABSTRACT
BACKGROUND: An eco-friendly analytical technique was developed with the intention of preserving the environment by using green chemistry principles. Pemetrexed is a folate analogue indicated for the treatment of advanced lung cancer. OBJECTIVE: Development of a green stability-indicating HPLC method for the quantification of pemetrexed ditromethamine (PDT) impurities in Active Pharmaceutical Ingredient (API) and parenteral dosage form. METHODS: Chromatographic separation was achieved using a Zorbax SB C18 column (150 mm × 4.6 mm i.d., 3.5 µ particle size) with perchlorate buffer (pH 3.0 ± 0.1, 50 mM) as mobile phase A and acetonitrile-perchlorate (90 + 10, v/v) buffer as mobile phase B at a flow rate of 0.8 mL/min with a column temperature of 40°C ± 0.5°C. All analytes were well resolved by gradient elution with a total run time of 75 min. The UV detection wavelength was 230 nm. RESULTS: The RP-HPLC method is capable of resolving all the degradation and process impurities for PDT API and parenteral dosage form. The related compounds method was validated in accordance with International conference on harmonization (ICH) Q2(R1) and United states of Pharmacopoeia (USP) <1225> guidelines, and found to be accurate, specific, precise, linear, robust and stability-indicating. The precision and intermediate results were <5% CV for all the impurities. The accuracy for all the impurities was found to be between 90 and 110%. The linearity of regression co-efficient values for all the impurities were found to be more than 0.999. CONCLUSION: The proposed related compounds method is found suitable for the determination of process and degradation impurities of commercial formulations, stability samples in QC analysis for PDT API, and drug product. HIGHLIGHTS: The developed liquid chromatographic method greenness and eco-friendliness were assessed using the green analytical procedure index (GAPI) and the analytical greenness (AGREE) tool, and found to be green. A PDT detoxification procedure was also developed to reduce environmental pollution.
Subject(s)
Antineoplastic Agents , Drug Stability , Pemetrexed , Chromatography, High Pressure Liquid/methods , Pemetrexed/analysis , Pemetrexed/chemistry , Antineoplastic Agents/analysis , Antineoplastic Agents/chemistry , Green Chemistry Technology/methods , Drug Contamination , InjectionsABSTRACT
An individual's therapeutic drug exposure level is directly linked to corresponding clinical effects. Rapid, sensitive, inexpensive, portable and reliable devices are needed for diagnosis related to drug exposure, treatment, and prognosis of diseases. Electrochemical sensors are useful for drug monitoring due to their high sensitivity and fast response time. Also, they can be combined with portable signal read-out devices for point-of-care applications. In recent years, nanomaterials such as carbon-based, carbon-metal nanocomposites, noble nanomaterials have been widely used to modify electrode surfaces due to their outstanding features including catalytic abilities, conductivity, chemical stability, biocompatibility for development of electrochemical sensors. This review paper presents the most recent advances about nanomaterials-based electrochemical sensors including the use of green assessment approach for detection of drugs including anticancer, antiviral, anti-inflammatory, and antibiotics covering the period from 2019 to 2023. The sensor characteristics such as analyte interactions, fabrication, sensitivity, and selectivity are also discussed. In addition, the current challenges and potential future directions of the field are highlighted.
Subject(s)
Electrochemical Techniques , Nanostructures , Nanostructures/chemistry , Humans , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/analysis , Anti-Bacterial Agents/analysis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Green Chemistry Technology , Biosensing Techniques , Anti-Inflammatory Agents/analysis , Anti-Inflammatory Agents/chemistry , Antiviral Agents/chemistry , Antiviral Agents/analysis , Antiviral Agents/pharmacologyABSTRACT
Dentro da área da nanotecnologia, o sistema drug delivery vem sendo amplamente utilizado, cujo objetivo é proporcionar uma maior eficácia dos ativos farmacêuticos, podendo envolver desde uma distribuição mais seletiva dentro do organismo até a taxa que as moléculas serão liberadas e/ou a atenuação dos efeitos adversos provocados. Para isso, os ativos são encapsulados em nanoestruturas, podendo estas serem de natureza sintética ou natural. Dentre os nanocarreadores promissores encontram-se os cubossomos, que são nanoestruturas complexas capazes de encapsular ativos tanto hidrofílicos quanto hidrofóbicos. O objetivo deste projeto foi estudar a encapsulação de fármacos antineoplásicos em sistemas drug delivery contra linhagens celulares, investigando também as alterações estruturais sofridas pelos cubossomos e os efeitos sinérgicos dos fármacos, sendo eles: a doxorrubicina, a cisplatina, a vemurafenibe e a curcumina. As metodologias empregadas para elucidar o efeito das combinações dos fármacos, a estruturação da nanopartícula e sua citotoxicidade foram: os estudos de viabilidade celular pós-exposição, espalhamento dinâmico de luz, potencial zeta, análise de rastreamento de nanopartículas, espalhamento de raios-x a baixos ângulos, criomicroscopia eletrônica de transmissão, eficiência de encapsulação e ensaio de liberação. Inicialmente os fármacos foram testados isoladamente e em duplas, sendo utilizadas cinco linhagens celulares, afim de se promover um delineamento aos ensaios futuros. A partir destes resultados, foi-se optado por manter duas linhagens celulares, a HeLa, como representante de tecidos tumorais, e a HaCat, modelo de tecido saudável, devido a menor resistência apresentada por elas. Em relação as combinações entre as drogas, pode-se observar que todas as duplas formadas apresentaram resultados sinérgicos na linhagem tumoral, sendo mantida para os testes seguintes a combinação curcumina e vemurafenibe. Os cubossomos foram sintetizados eficientemente, sendo produzidos na ausência de fármacos bem como contendo curcumina e vemurafenibe. As nanopartículas apresentaram uma variação de diâmetro entre 189 ± 3 nm e 224 ± 2 nm, sendo o PDI entre 0,08 e 0,25. A conformação do cubossomo foi confirmada através da criomicroscopia eletrônica de transmissão e pelo espalhamento de raios-x a baixos ângulos, onde foi determinada uma estruturação característica de Pn3m. Para a eficiência de encapsulação os valores variaram entre 79% de encapsulação para a curcumina e 72% para a vemurafenibe, quando utilizadas isoladamente. No caso da encapsulação em dupla, os valores se converteram para 63% e 53% para a curcumina e vemurafenibe, respectivamente. A liberação das drogas do interior da nanopartícula oscilou entre 1500, 480 e 420 minutos para os cubossomos de curcumina, vemurafenibe e curcumina + vemunafenibe, respectivamente. Os testes de citotoxicidade demonstraram que as concentrações de 0,01 e 0,03 mg/mL foram capazes de promover uma viabilidade acima de 70%, porém, utilizando estas proporções não foi possível observar resultados significativos. Por fim, o sistema se mostrou estável e homogêneo, sendo capaz de promover a encapsulação dos fármacos tanto singularmente quanto em dupla e, apesar da quantidade de fármacos não ter sido suficiente para ocasionar alterações ao sistema celular, a execução deste trabalho abre portas para que novos estudos sejam realizados, podendo-se testar diferentes ativos bem como alterando a composição da nanopartícula afim de se reduzir a citotoxicidade
Within the area of nanotechnology, the drug delivery system has been widely used, whose objective is to provide greater effectiveness of pharmaceutical active ingredients, which may range from a more selective distribution within the organism to the rate at which the molecules will be released and/or the attenuation of adverse effects caused. To achieve this, the active ingredients are encapsulated in nanostructures, which may be synthetic or natural in nature. Among the promising nanocarriers are cubosomes, which are complex nanostructures capable of encapsulating both hydrophilic and hydrophobic active ingredients. The objective of this project was to study the encapsulation of antineoplastic drugs in drug delivery systems against cell lines, also investigating the structural changes undergone by the cubosomes and the synergistic effects ofthe drugs, namely: doxorubicin, cisplatin, vemurafenib and curcumin. The methodologies used to elucidate the effect of drug combinations, the structuring of the nanoparticle and its cytotoxicity were: post-exposure cell viability studies, dynamic light scattering, zeta potential, nanoparticle tracking analysis, small angle x-rays scattering, transmission electron cryomicroscopy, encapsulation efficiency and release assay. Initially, the drugs were tested alone and in pairs, using five cell lines, in order to promote a design for future trials. Based on these results, it was decided to maintain two cell lines, HeLa, as a representative oftumor tissues, and HaCat, a model ofhealthy tissue, due to their lower resistance. Regarding the combinations between the drugs, it can be observed that all the pairs formed presented synergistic results in the tumor lineage, with the combination of curcumin and vemurafenib being maintained for the following tests. Cubosomes were efficiently synthesized, being produced in the absence of drugs as well as containing curcumin and vemurafenib. The nanoparticles varied in diameter between 189 ± 3 nm and 224 ± 2 nm, with the PDI being between 0.08 and 0.25. The conformation ofthe cubosome was confirmed through transmission electron cryomicroscopy and small angle x-rays scattering, where a characteristic structure of Pn3m was determined. For encapsulation efficiency, values varied between 79% encapsulation for curcumin and 72% for vemurafenib, when used alone. ln the case of double encapsulation, the values converted to 63% and 53% for curcumin and vemurafenib, respectively. The release of drugs from the interior of the nanoparticle ranged between 1500, 480 and 420 minutes for the curcumin, vemurafenib and cubosomes with curcumin + vemunafenib, respectively. Cytotoxicity tests demonstrated that concentrations of 0.01 and 0.03 mg/mL were capable of promoting viability above 70%, however, using these proportions it was not possible to observe significant results. Finally, the system proved to be stable and homogeneous, being able to promote the encapsulation of drugs both singly and in pairs and, although the quantity of drugs was not enough to cause changes to the cellular system, the execution of this work opens doors for new studies are carried out, with the possibility oftesting different active ingredients as well as changing the composition of the nanoparticle in order to reduce cytotoxicity