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In the present work, a reduced graphene oxide (rGO) modified-Fe 3 O 4 doped bifunctional carbon felt cathode (rGO-Fe 3 O 4 /CF) that is capable of generating and converting H 2 O 2 into hydroxyl radicals ( • OH) on-site was fabricated, thus removing the need for an external catalyst. In addition, an rGO-modified cathode (rGO/CF) with high H 2 O 2 production efficiency and a heterogeneous Fenton catalyst (CNT-Fe 3 O 4 ) with magnetic properties were fabricated. The study examined the degradation and mineralization of the cytostatic drug cytarabine (CYT) using two HEF configurations: (i) a bifunctional cathode rGO-Fe 3 O 4 /CF and (ii) a combination of the rGO/CF cathode with CNT-Fe 3 O 4 catalyst. The effects of parameters such as catalyst concentration, initial pH, and applied current were studied. HPLC and ion chromatography analyses were used to identify carboxylic acids and inorganic end-products, respectively. The results show that 0.1 mM CYT was completely degraded within 18 min at an applied current of 300 mA in the HEF system with the rGO-Fe 3 O 4 /CF bifunctional cathode. Total organic carbon (TOC) analysis revealed that the bifunctional cathode system achieved 98.2% mineralization of CYT after 4 h of treatment at 300 mA. Using the rGO/CF cathode and CNT-Fe 3 O 4 catalyst cell, total degradation of 0.1 mM CYT occurred within 7 min, and nearly total mineralization (97.3% TOC removal) was achieved at 300 mA after 4 h., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

VYXEOS® is the first FDA-approved dual-API liposomal formulation containing two different chemotherapeutics, daunorubicin and cytarabine at a 1:5 molar ratio. Analysis of bulk formulation does not provide insight to size-based distribution of APIs and excipients, therefore asymmetrical flow field-flow fractionation (AF4) was utilized for the size-based separation of VYXEOS® liposomes and collected size fractions were further analyzed for the concentrations of APIs, lipid excipients, and copper. Analysis results revealed a significant variation in API distribution across the size fractions, with the larger liposomes encapsulating a higher ratio of cytarabine to daunorubicin compared to the smaller liposomes, while lipid excipient composition was held constant across the size range. We attribute the size-based variation of API ratios to structural change during API loading and sequence of API loading. Cytarabine is first passively loaded into liposomes containing copper gluconate, and then daunorubicin is actively loaded using copper gradient where the daunorubicin is retained in the liposomes as a copper complex. This method can be extended to characterize various single and dual-API liposomal nanocarriers during drug product development and/or post market quality control., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

An integrated strategy by combining cocrystallization with nanotechnology is developed to optimize in vitro/vivo performances of marine antitumor drug cytarabine (ARA) and further obtain innovative insights into the exploitation of cocrystal alloy nanoformulation. Therein, the optimization of properties and synergistic effects of ARA mainly depends on assembling with uracil (U) and antitumor drug 5-fluorouracil (FU) into the same crystal by cocrystallization technology, while the long-term efficacy is primarily maintained by playing the superiority of nanotechnology. Along this line, the first cocrystal alloy of ARA, viz. , ARA-FU-U (0.6:0.4), is successfully obtained and then transformed into a nanocrystal. Single-crystal X-ray diffraction analysis demonstrates that this cocrystal alloy consists of two isomorphic cocrystals of ARA, namely, ARA-FU and ARA-U, in 0.6:0.4 ratio. An R 2 2 (8) hydrogen-bonding cyclic system formed by a cytosine fragment of ARA with U or FU can protect and stabilize the amine group on ARA, laying the foundation for regulating its properties. The in vitro / in vivo properties of the cocrystal alloy and its nanocrystals are investigated by theoretical and experimental means. It reveals that both the alloy and nanocrystal can improve physicochemical properties and promote drug absorption, thus bringing to optimized pharmacokinetic behaviors. The nanocrystal produces superior effects than the alloy that helps to extend therapeutic time and action. Particularly, relative to the corresponding binary cocrystal, the synergistic antitumor activity of ARA and FU in the cocrystal alloy is heightened obviously. It may be that U contributes to reducing the degradation of FU, specifically increasing its concentration in tumors to enhance the synergistic effects of FU and ARA. These findings provide new thoughts for the application of cocrystal alloys in the marine drug field and break fresh ground for cocrystal alloy formulations to optimize drug properties.

Acute myeloid leukemia (AML) is a hematological malignancy with a high recurrence rate. The interaction of chemokine receptor 4/chemokine ligand 12 (CXCR4/CXCL12) mediates homing and adhesion of AML cells in bone marrow, leading to minimal residual disease in patients, which brings a hidden danger for future AML recurrence. Ara-C is a nonselective chemotherapeutic agent against AML. Due to its short half-life and severe side effects, a lipid-like Ara-C derivative (AraN) was synthesized and a dual-function LipoAraN-E5 (135 nm, encapsulation efficiency 99%) was developed, which coloaded AraN and E5, a peptide of the CXCR4 antagonist. LipoAraN-E5 effectively improved the uptake, enhanced the inhibition of leukemia cell proliferation, migration, and adhesion to stromal cells in bone marrow, and mobilized the leukemia cells from bone marrow to peripheral blood via interfering with the CXCR4/CXCL12 axis. LipoAraN-E5 prolonged the plasma half-life of AraN (8.31 vs 0.56 h) and was highly enriched in peripheral blood (3.67 vs 0.05 μmol/g at 8 h) and bone marrow (379 vs 148 μmol/g at 24 h). LipoAraN-E5 effectively prevented the infiltration of leukemia cells in peripheral blood, bone marrow, spleen, and liver, prolonged the mice survival, and showed outstanding antineoplastic efficacy with negligible toxicity, which were attributed to the ingenious design of AraN, the use of a liposomal delivery carrier, and the introduction of E5. Our work revealed that LipoAraN-E5 may be a promising nanocandidate against AML.

Environmental release of wastewater that contains cytostatic drugs can cause genotoxic impact, since these drugs act directly on the genetic material of aquatic organisms. Thus, the aim of this study was to evaluate the removal of the cytostatic drugs cytarabine (CTR) and methotrexate (MTX) using different physico-chemical methods individually (i.e. US, O 3 , H 2 O 2 and UV) and combined (i.e. O 3 /US, US/H 2 O 2 , O 3 /H 2 O 2 and O 3 /US/H 2 O 2 ) under different pH conditions (4, 7 and 10). In the degradation tests, the efficiency of the methods applied was found to be dependent on the pH of the solution, with the degradation of CTR being better at pH 4 and MTX at pH 7 and pH 10. The US, H 2 O 2 and US + H 2 O 2 methods were the least efficient in degrading CTR and MTX under the pH conditions tested. The highest MTX degradation rate after 16 min of treatment at pH 7 was achieved by the O 3  + H 2 O 2 method (97.05% - C/C 0  = 0.0295). For CTR, the highest degradation rate after 16 min of treatment was achieved by the O 3 process (99.70% - C/C 0  =  0.0030) at pH 4. In conclusion, most of the treatment methods tested for the degradation of CTR and MTX are effective. Notably, ozonolysis is an efficient process applied alone. Also, in combination with other methods (US + O 3 , O 3  + H 2 O 2 and O 3  + H 2 O 2  + US) it increases the degradation performance, showing a rapid removal rate of 70-94% in less than 4 min of treatment.

Herein, a turn "Off/On" fluorescence probe based on ZnO quantum dots (ZnO-QDs) has been proposed and successfully utilized for the determination of Ara-C (cytarabine) using ceric ions (Ce 4+ ) as quencher and ethylenediamine (ED) as a linker. The probe is based initially on the quenching effect of Ce 4+ ions on the strong native fluorescence of ZnO-QDs forming the Turn Off system (Ce@ZnO-QDs) that believed to occur due to the aggregation-induced quenching (AIQ) mechanism. The second step is the addition of Ara-C in the presence of ethylenediamine (ED) that encourages the formation of Ara-C/ED/Ce 4+ as well as the release of the free ZnO-QDs, leading to the recovery of the fluorescence intensity. The developed sensing platform shows a linear response towards Ara-C over the range of 10 to 1000 ng mL -1 giving a limit of detection (LOD) and limit of quantitation (LOQ) of 1.22 ng mL -1 and 3.70 ng mL -1 , respectively. A dispersive magnetic solid phase micro-extraction (dMSPE) method was developed and optimized for the extraction of Ara-C in spiked human plasma using thiol-modified magnetite nanoparticles (S-MNPs). The proposed platform exhibits good sensitivity toward Ara-C in the presence of different interfering substances. Excellent recoveries are obtained after spiking different concentrations of Ara-C into rabbit plasma samples. The validated experimental parameters have been successfully applied to monitor the pharmacokinetic profile of Ara-C in rabbit plasma. A detailed adsorption kinetics study has been carried out to provide a deep insight into the adsorption behavior of Ara-C on the thiol-doped-magnetite nanoparticles. The greenness assessment of the proposed method was achieved and compared with other reported methods using two tools of greenness; the green analytical procedure index (GAPI) and the analytical greenness calculator AGREE., (© 2023. The Author(s).)

Nucleoside analogue drugs are pervasively used as antiviral and chemotherapy agents. Cytarabine and gemcitabine are anti-cancer nucleoside analogue drugs that contain C2' modifications on the sugar ring. Despite carrying all the required functional groups for DNA synthesis, these two compounds inhibit DNA extension once incorporated into DNA. It remains unclear how the C2' modifications on cytarabine and gemcitabine affect the polymerase active site during substrate binding and DNA extension. Using steady-state kinetics, static and time-resolved X-ray crystallography with DNA polymerase η (Pol η) as a model system, we showed that the sugar ring C2' chemical groups on cytarabine and gemcitabine snugly fit within the Pol η active site without occluding the steric gate. During DNA extension, Pol η can extend past gemcitabine but with much lower efficiency past cytarabine. The Pol η crystal structures show that the -OH modification in the β direction on cytarabine locks the sugar ring in an unfavorable C2'-endo geometry for product formation. On the other hand, the addition of fluorine atoms on gemcitabine alters the proper conformational transition of the sugar ring for DNA synthesis. Our study illustrates mechanistic insights into chemotherapeutic drug inhibition and resistance and guides future optimization of nucleoside analogue drugs., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

DNA polymerase η (polη) is of significant value for designing new families of anticancer drugs. This protein takes a role in many stages of the cell cycle, including DNA replication, translesion DNA synthesis, and the repairing process of DNA. According to many studies, a high level of expression of polη in most cases has been associated with low rates of patients' survival, regardless of considering the stage of tumor cells. Thus, the design of new drugs with fewer side effects to inhibit polη in cancerous cells has attracted attention in recent years. This project aims to design and explore the alternative inhibitors for polη, which are based on carbohydrates and amino acids. In terms of physicochemical properties, they are similar to the traditional anticancer drugs such as Cytarabine (cytosine arabinose). These alternative inhibitors are supposed to disrupt the DNA replication process in cancerous cells and prevent the tumor cells from mitosis. These newly designed structures, which are based on natural products, are expected to be non-toxic and to have the same chemotherapeutic impact as the traditional agents. The combinatorial use of quantum mechanics studies and molecular dynamic simulation has enabled us to precisely predict the inhibition mechanism of the newly designed structure, which is based on carbohydrates and amino acids, and compare it with that of the traditional chemotherapeutic drugs such as Cytarabine. Our results suggest that the inhibitors containing the natural building blocks of amino acid and carbohydrate could be considered alternative drugs for Cytarabine to block polη., (© 2022. The Author(s).)