Chasing Graphene-Based Anticancer Drugs: Where are We Now on the Biomedical Graphene Roadmap?

Katarzyna Uzdrowska,1 Narcyz Knap,1 Jacek Gulczynski,2 Alicja Kuban-Jankowska,1 Wiktoria Struck-Lewicka,3 Michal J Markuszewski,3 Tomasz Bączek,3 Ewa Izycka-Swieszewska,2 Magdalena Gorska-Ponikowska1 1Department of Medical Chemistry, Medical University of Gdansk, Gdansk, 80-211, Poland; 2Faculty of Health Sciences with the Institute of Maritime and Tropical Medicine, Medical University of Gdansk, Gdansk, 80-211, Poland; 3Faculty of Pharmacy, Medical University of Gdansk, Gdansk, 80-416, PolandCorrespondence: Magdalena Gorska-Ponikowska, Department of Medical Chemistry, Medical University of Gdansk, 1 Debinki St, Gdansk, 80-211, Poland, Tel +48 58 349 14 50, Fax +48 58 349 14 56, Email [email protected]: Graphene and graphene-based materials have attracted growing interest for potential applications in medicine because of their good biocompatibility, cargo capability and possible surface functionalizations. In parallel, prototypic graphene-based devices have been developed to diagnose, imaging and track tumor growth in cancer patients. There is a growing number of reports on the use of graphene and its functionalized derivatives in the design of innovative drugs delivery systems, photothermal and photodynamic cancer therapy, and as a platform to combine multiple therapies. The aim of this review is to introduce the latest scientific achievements in the field of innovative composite graphene materials as potentially applied in cancer therapy. The “Technology and Innovation Roadmap” published in the Graphene Flagship indicates, that the first anti-cancer drugs using graphene and graphene-derived materials will have appeared on the market by 2030. However, it is necessary to broaden understanding of graphene-based material interactions with cellular metabolism and signaling at the functional level, as well as toxicity. The main aspects of further research should elucidate how treatment methods (e.g., photothermal therapy, photodynamic therapy, combination therapy) and the physicochemical properties of graphene materials influence their ability to modulate autophagy and kill cancer cells. Interestingly, recent scientific reports also prove that graphene nanocomposites modulate cancer cell death by inducing precise autophagy dysfunctions caused by lysosome damage. It turns out as well that developing photothermal oncological treatments, it should be taken into account that near-infrared-II radiation (1000– 1500 nm) is a better option than NIR-I (750– 1000 nm) because it can penetrate deeper into tissues due to less scattering at longer wavelengths radiation.Keywords: graphene-based materials, oncological therapies, cancer treatment, biomedical innovations, drugs delivery system

Simultaneous determination of creatinine and acetate by capillary electrophoresis with contactless conductivity detector as a feasible approach for urinary tract infection diagnosis

Urinary tract infection (UTI) is one of the most common bacterial infection in human but its diagnosis is difficult. Metabolomic studies with nuclear magnetic resonance of urine have shown that acetic acid/creatinine ratio may be used for early UTI diagnosis. Here, a method for simultaneous determination of acetate and creatinine by capillary zone electrophoresis with contactless conductivity detector was developed for the first time. The separation was with 40 mM MES and 20 mM L-histidine as a background solution. The total time of a single run, including capillary conditioning, was less than 12 min. The method was successfully demonstrated for analysis of actual and fortified human urine samples after methanol dilution. Analytical figures of merit such as linearity, LOQ, and repeatability (intraday and interday) were studied

Different detection and stacking techniques in capillary electrophoresis for metabolomics

In the last decade, capillary electrophoresis (CE) has joined other analytical separation techniques that are widely used in metabolomics. The coupling of CE with mass spectrometry (MS) as a detector has become a gold standard. However, many other detection techniques can be also employed, especially in non-targeted metabolomics. In addition, CE offers various stacking approaches that improve the sensitivity. Here, we highlight the use of non-MS detectors as well as stacking approaches in metabolomics since 2014

Sample concentration of charged small molecules and peptides in capillary electrophoresis by micelle to cyclodextrin stacking

A stacking approach in capillary electrophoresis based on the reversal of the analytes’ effective electrophoretic velocities at a dynamic stacking boundary formed between charged micelles (i.e., from long chain ionic surfactants) and neutral cyclodextrins (i.e., native α-, β-, or γ-cyclodextrin) is presented. The approach was demonstrated by the long injection of samples in a micellar solution followed by injection of a cyclodextrin solution zone, and then separation by co-electro-osmotic flow capillary zone electrophoresis. The reversal is caused by the formation of stable cyclodextrin–surfactant complexes at the boundary that significantly decreased the retention factor of the analytes in the presence of a micellar pseudostationary phase. The dynamic boundary was formed at the cyclodextrin zone as the micelles penetrated this zone. Under optimum conditions, the boundary disappears, and the stacking ends when all the micelles have electrophoretically migrated to the boundary. Cationic and anionic small molecules were enriched using oppositely charged micelles from sodium dodecyl sulfate and cetyltrimethylammonium bromide, respectively. There were 1–2 orders of concentration magnitude improvement in analyte detection, which is expected in stacking with hydrodynamic injection. The improvements in the peak signals (height/corrected area) were up to 236/445 and 101/76 for the cationic and anionic analytes tested, respectively. Linearity (r2) and repeatability (%RSD of migration time, peak height, and corrected peak area) under the chosen stacking conditions (cations/anions) were ≥0.998/≥0.995 and ≤3.8%/≤5.7%, respectively. The stacking approach was also implemented in the direct analysis of peptides from trypsin digested bovine serum albumin

Multidimensional Capillary Electrophoresis

Multidimensional (MD) separation is a combination of two or more separation techniques that increases peak capacity. There are two requirements or criteria in MD as suggested by Giddings. First is orthogonality, which means that the separation mechanism in each step must be based on different molecular properties such as size, charge, hydrophobicity, or chirality. Second is that the separation obtained in the first dimension must be preserved in the subsequent dimensions. There are two types of MD separation, comprehensive and heart cutting. In the first type, all compounds present in the mixture are separated and detected, while in the second, only selected fractions in the mixture are analyzed. The connection between the dimensions that must be tight and dead-volume free is the most important part of an MD separation system. The most common connection was an interface that joins two or more chromatographic columns and/or electrophoretic capillaries. In the case of capillary electrophoresis (CE), there is an alternative strategy to obtain MD separations without the use of an interface. This is the so-called heart-cutting MD-CE in a single capillary or interface-free MD-CE. In interface-free MD-CE, mobilization of fractions between dimensions is achieved by manipulation of voltage and/or pressure. Although MD-CE has been developed for more than 15 years, applications to real samples were not as prevalent as those reported for MD gas and liquid chromatography. MD-CE research reports were on tighter interfaces development as well as sensitivity and performance enhancements in two-dimension format (2D-CE). This article is devoted to the wide range of interfaces and interface/interface-free methods developed for 2D-CE. CE separation modes used in 2D-CE were also briefly discussed for readers not familiar with CE

Field enhanced sample injection for the CE determination of arsenic compounds using successive multiple ionic polymer layer coated capillaries

A capillary electrophoresis method using indirect UV detection has been applied to the determination of arsenate [As(V)], arsenite [As(III)], monomethylarsonic acid and dimethylarsinic acid. The arsenic species were successfully separated in a successive multiple ionic polymer layer coated capillary. On-line sample preconcentration of arsenic compounds were performed by employing field enhanced sample injection. A baseline separation was achieved in a basic background solution of 10 mM 2,6-pyridinedicarboxylic acid at pH 10.3. The precision of migration time was 1.2-2.4% RSD and peak height was 8.1-12.9% RSD. The limits of detection at a S/N ratio of 3 for the four arsenic compounds were found to be 20-70 ppb, which are comparable to other on-line preconcentration techniques. The enhancement factor was improved by 230-1,500-fold

Urinary Nucleosides as Biomarkers of Breast, Colon, Lung, and Gastric Cancer in Taiwanese

Urinary nucleosides are associated with many types of cancer. In this study, six targeted urinary nucleosides, namely adenosine, cytidine, 3-methylcytidine, 1-methyladenosine, inosine, and 2-deoxyguanosine, were chosen to evaluate their role as biomarkers of four different types of cancer: lung cancer, gastric cancer, colon cancer, and breast cancer. Urine samples were purified using solid-phase extraction (SPE) and then analyzed using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The Mann-Whitney U test and Principal Component Analysis (PCA) were used to compare differences in urinary nucleosides between patients with one of four types of cancer and healthy controls. The diagnostic sensitivity of single nucleosides for different types of cancer ranged from 14% to 69%. In contrast, the diagnostic sensitivity of a set of six nucleosides ranged from 37% to 69%. The false-positive identification rate associated with the set of six nucleosides in urine was less than 2% compared with that of less than 5% for a single nucleoside. Furthermore, combining the set of six urinary nucleosides with carcinoembryonic antigen improved the diagnostic sensitivity for colon cancer. In summary, the study show that a set of six targeted nucleosides is a good diagnostic marker for breast and colon cancers but not for lung and gastric cancers