Anticancer 5-fluorouracil Research Articles

Controlled anticancer 5-Fluorouracil release from functionalized 5-FU/PLGA/CaP coating on titanium implants: Characterization, in vitro drug delivery and cytotoxicity

Work presents a novel approach for creating anticancer coatings on titanium implants using 5-Fluorouracil (5-FU) loaded in calcium phosphate which is encapsulated in poly(lactic-co-glycolic acid) (PLGA/CaP) for controllable drug release. Our method involves the hybrid ultrasound-assisted micro-arc oxidation (UMAOH) technique, which make use of an ultrasound as an additional means of energy input resulting in increased pore size, drug deposition, and layer-by-layer self-assembly of PLGA. The multilayer coatings exhibit amorphous-crystalline structure with dicalcium phosphate anhydrous (DCPA) and β-tricalcium phosphate (β-TCP) phases, Ca/P ratio of 0.3, surface roughness (Ra) of 2.3–3.5 µm, and thickness between 52–60 µm. Drug release kinetics revealed a burst release for 5FU/CaP in the initial 10–20 min and sustained release over 2–4 h. 5FU/PLGA/CaP displayed a smooth, sustained release over 5 days. Biocompatibility studies showed that extracts from drug-free CaP and CaP/PLGA samples were nontoxic to HeLa, NIH-3Т3, and MCF-7 cell lines (≥ 80 % cell viability) for 0.2–24 h. In contrast, extracts from drug-loaded carriers were cytotoxic to NIH-3T3 cells (> 60 % cell death). Notably, 5-FU impregnation in the CaP coting demonstrated varying cytotoxicity, with the following cell death order: 75 % HeLa > 68 % NIH-3Т3 > 59 % MCF-7. PLGA modification reduced cytotoxicity with the following cell death order: 61 % HeLa > 52 % NIH-3Т3 > 46 % MCF-7. This work presents a promising strategy for localized, controlled drug delivery 5FU/PLGA/CaP system, with reduced cytotoxicity compared to PLGA-free 5-FU/CaP coating, advancing implant-based cancer treatment.

Metalloborospherenes as a potential promising high drug-loading capacity for anticancer 5-fluorouracil drug: A DFT mechanistic approach

The potential of exohedral metalloborospherene (Na@B40, Mg@B40, Fe@B40, Fe4@B40 and Fe6@B40) for delivery of anti-cancer 5-fluorouracil (5FU) have been investigated using DFT calculations. The NBO analysis, statistical thermodynamics, PDOS characteristics, NCI and QTAIM descriptors of these systems were investigated to analyze the interaction process. UV–visible electronic absorption spectra in the gas and aqueous phases were simulated using TD-DFT calculations.In addition, to examine the drug-loading capacity and biocompatibility, up to six 5FU molecules can be attached to Fe6@B40. The solvent effects tend to lower the 5FU adsorption energies to be easily released from nanocages. The greater polarizability and first hyperpolarizability of the 5FU@[Mg@B40], (5FU)4@[Fe4@B40] and (5FU)6@[Fe6@B40] systems imply their applications in photonic and extremely effective to improve the NLO performance. These theoretical identifications can provide new insights and guidelines for the future experimental researchers to promote the synthesis and application of metalloborospherenes (Fe4@B40 and Fe6@B40) in drug-loading capacity.

Efficient delivery of anticancer 5-fluorouracil drug by alkaline earth metal functionalized porphyrin-like porous fullerenes: A DFT study

Finding and developing effective targeted drug delivery systems has emerged as an attractive approach for treating a wide range of diseases. In the present study, the potential of alkaline earth metal functionalized porphyrin-like porous C24N24 fullerenes for delivering 5-fluorouracil (5FU) anticancer drug is assessed using density functional theory calculations. The goal is to evaluate how the addition of alkaline earth metals to C24N24 enhances the adsorption capabilities of this system towards 5FU drug. The adsorption energies and charge transfers are determined in order to evaluate the strength of the interaction between the 5FU and fullerene surfaces. According to the results, adding alkaline earth metals increases the drug's adsorption energy on the C24N24 fullerene. In all cases, the drug molecule interacts with the metal atom through its CO group. Furthermore, the adsorption strength of the 5FU increases with metal atom size (Ca > Mg > Be), which is connected to the polarizability of these atoms. The adsorption energies of 5FU are shown to be highly sensitive on solvent effects and the acidity of the environment. The adsorption strength of 5FU decreases within the solvent (water), allowing it to be released more easily. The moderate adsorption energies and short desorption times of 5FU imply that it is reversibly adsorbed on the functionalized fullerenes.

Preparation and characterization of magnetic nanohydrogel based on chitosan for 5-fluorouracil drug delivery and kinetic study

Chemotherapy is currently used for most cancer treatments, but one of the significant problems of this treatment is that it affects the healthy tissues of the body. Therefore, designing new systems for the intelligent and controlled release of these drugs in cancer tissues is one of the major challenges in the world. Hence, today, huge costs are spent designing appropriate new drug delivery systems (DDS) with controlled drug release. In this study, chitosan-polyacrylic acid encapsulated Fe3O4 magnetic nanogelic core-shell (Fe3O4@CS-PAA) was synthesized in the presence of glutaraldehyde used for loaded anticancer 5-fluorouracil (5-FU) drug. Also, the prepared Fe3O4@CS-PAA was characterized by using FT-IR, SEM, XRD, and VSM analysis. Then, drug delivery tests were carried out in the in-vitro conditions that are the simulated physiological environment and tumor tissue conditions. The drug release tests indicated that the Fe3O4@CS-PAA upgraded the rate of 5-FU release from nanogelic core-shell under tumor tissue conditions (pH 4.5) than physiological environments (pH 7.4). In addition, various models were used to investigate the drug release mechanism. Results of modeling studies of drug release showed the mechanism of 5-FU release from Fe3O4@CS-PAA controlled by Fickian diffusion.

Efficient carriers for anticancer 5-fluorouracil drug based on the bare and M−encapsulated (M = Na and Ca) B40 fullerenes; in silico investigation

In this work, density functional theory (DFT) calculations are being made to investigate the interaction between the 5-fluorouracil (FU) anticancer drug with the bare and M−encapsulated (M = Na and Ca) all-boron B40 fullerenes. Our results reveal that the FU drug remarkably interacts with both bare and encapsulated fullerene. The electronic structure of the fullerenes is significantly affected via interaction with the FU drug molecule. The decrease of the energy gap of the stable complexes can be used as a chemical signal for determining the FU drug adsorption. The adsorption of six fluorouracil molecules on the top of the Na and Ca encapsulated B40 shows greater adsorption energy than bare fullerene in the gas and water phases. Also, the high dipole moments are found for the considered complexes in the water phase. Consequently, Na@B40 and Ca@B40 are introduced as promising innovative candidates for drug delivery of the Fu molecule due to their strong adsorption energies and great solubility in the polar medium. The results might open new windows in the nanomedicine domain.

Mechanical characterization of bio composite films as a novel drug carrier platform for sustained release of 5-fluorouracil for colon cancer: Methodological investigation

In this study, we employed Pectin (PC) as a matrix that is hybridized with three different nucleobase (NB) units (cytosine, thymine, uracil) to generate pectin–nucleobase(PC-NB) biocomposite films stabilized through bio-multiple hydrogen bonds (BMHBs) as drug carrier for anticancer 5-Fluorouracil (5-FU). Prepared biocomposite films were characterized by Fourier Transform Infra-red Spectroscopy (FTIR), X-ray Diffraction (XRD), Thermogravimmetry Analysis (TGA) and Scanning Electron Microscope (SEM). Mechanical and sorption properties were also evaluated. In vitro drug release performed in both acidic pH 1.2 (stomach pH) and alkaline pH 7.4 (intestinal pH) showed that incorporation of nucleobases into pectin significantly restricted release rate of 5-FU particularly under acidic condition (pH 1.2). Hemolysis assays demonstrated that PC-NB-5-FU biocomposite film drug carriers were hemocompatible. Confocal microscope analysis indicates facilitated cellular uptake of PC-NB-5-FU film in HT-29 colon cancer cell line, which in turn result in a higher potential of apoptosis. Confocal imaging of fluorescent live/dead cell indicators and MTT assay outcomes, both demonstrated significant decreases in cellular viability of PC-NB-5-FU biocomposite films. Collectively, our findings indicate that this PC-NB-5-FU biocomposite films can be conferred as a proficient formulation for targeted delivery of colon cancer drugs.

Chitosan-Functionalized Mg0.5Co0.5Fe2O4 Magnetic Nanoparticles Enhance Delivery of 5-Fluorouracil In Vitro

Magnetic nanoparticles (MNPs) have been widely investigated as a strategy to improve the delivery efficiency of therapeutic and diagnostic agents. Substituted iron oxides or ferrite nanoparticles (NPs) such as CoFe2O4 represent an interesting and novel class of MNPs, although they are under-researched in the field of biomedicine. In this study, chitosan-functionalized Mg0.5Co0.5Fe2O4 NPs were loaded with the anti-cancer 5-fluorouracil (5-FU) drug to yield CS-Mg0.5Co0.5Fe2O4-5FU. Transmission electron microscopy (TEM), Fourier Transform infra-red (FTIR) spectroscopy and nanoparticle tracking analysis (NTA) were employed to determine the physiochemical properties of the NPs. Physico-chemical characterizations confirmed spherical NPs with particle sizes of approximately 20.39 nm. Improved colloidal stability was observed, as determined by a zeta potential of approximately −20 mV for the drug-loaded CS-Mg0.5Co0.5Fe2O4 NPs. Drug encapsulation efficiencies of >60% were attained, showing a pH-dependent release of 5-FU. Cell viabilities investigated using the 3-[(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] (MTT) and sulforodhamine B (SRB) assays in human embryonic kidney (HEK293), human breast adenocarcinoma (MCF-7) and human cervical cancer (HeLa) cells showed that these drug-loaded NPs exhibited more targeted tumor-specific cytotoxicities compared to free drugs. CS-Mg0.5Co0.5Fe2O4-5-FU NPs displayed significant targeted delivery potential to the investigated cancer cell lines. Conclusively, these results suggest that the CS-Mg0.5Co0.5Fe2O4-5-FU NPs are promising therapeutic delivery systems in anti-cancer treatment.

5-aminopyrazole-conjugated gelatin hydrogel: A controlled 5-fluorouracil delivery system for rectal administration

In recent years, more interest was dedicated to drug delivery systems (DDSs) and targeting drugs to the colonic region of the gastrointestinal tract. For this purpose, 5-aminopyrazole-conjugated gelatin hydrogel (5-AP/G) was designed to load anticancer 5-fluorouracil (5-FU) drug through soaking in the solution of drug. By using various analyses, the prepared 5-AP/G was characterized. In-vitro drug release study was carried out in simulating the rectal conditions for establishing the productivity of the prepared novel anticancer agent. 5-AP/G showed a predictable drug release manner in the rectal conditions with notable cytotoxicity against human colon adenocarcinoma HT29 cells. According to the obtained results, 5-AP/G hydrogel as a rectal administration of 5-FU could potentially be proposed in DDS for the treatment of rectal cancer.

Estimating of the binding constant of the anticancer 5-fluorouracil with Samarium and Europium

The interaction between 5-fluorouracil (5-FU) and some rare earth metals namely samarium (III) and europium (III) was studied using UV–Visible spectrophotometry and high performance liquid chromatography (HPLC) with fluorescence detection. The synthesized complexes were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR) and liquid chromatography mass spectrometry (LC/MS/MS). UV–Vis spectroscopic data revealed that the binding between two trivalent lanthanides and 5-FU was static binding, with conditional binding constant K(Sm−5−FU) = 0.452 × 104 M−1 and K(Eu−5−FU) = 0.183 × 104 M−1. Data were comparable with the values obtained using HPLC. The powder X-ray diffraction pattern of the complexes was used to determine the cell parameters and the hkl indices together with their corresponding 2θ values. The thermodynamic parameter ΔG°, ΔH° and ΔS° were also calculated to be −19.928 J/mol, 0.002 KJ/mol, 69.977 J/K⋅mol and −17.498 J/mol, −1.494 KJ/mol, 62.459 J/K⋅mol for Sm (III) and Eu (III) respectively, indicating that the binding was spontaneous for both trivalent lanthanide, of endothermic and exothermic nature Sm (III)and Eu (III) respectively.

Different zeolite systems for colon cancer therapy: monitoring of ion release, cytotoxicity and drug release behavior

Three types of oral administrated micronized zeolites [ZSM-5, zeolite A and Faujasite NaX (ZSM-5, ZA and ZX, respectively)] were prepared as anticancer 5-fluorouracil (5-Fu) delivery systems for colon cancer treatment. They were prepared by economically widespread and cheap natural resource, kaolin, at low temperatures, using microwave advanced tool. The obtained powders were characterized by XRD, SEM/EDX and BET; meanwhile, their degradation was investigated in two gastric fluids; FaSSGF (pH 1.6) and FeSSGF (pH 5), through concentration measurement of their solution disintegrated elemental constituents of Na+, Al3+ and Si4+ ions. Also, the processes of drug release and mechanism in both solutions were investigated. Moreover, the inhibition action of 5-Fu-free and 5-Fu-conjugated zeolites on colon cancer cells (CaCo-2) was estimated. The results showed that, the prepared zeolites possessed high surface areas of 526, 250, and 578 m2/g for ZSM-5, ZA and ZX, respectively. Although, zeolite structures seemed significantly stable, their frameworks seemed more likely reactive with time. The ions and drug release for zeolites occurred in successively two stages and found to be pH dependent, where the drug and zeolite ions were significantly of higher values in the more acidic media of the gastric solution (pH 1.6) than those of the mild acidic one (pH 5). The obtained activity indicated no cytotoxic affinity for all the prepared zeolite types. Accordingly, the synthesized zeolite frameworks are proposed to be of strong potential drug delivery vehicle for the treatment of gastrointestinal cancer.Graphical abstract

Genomic and tumor biological aspects of the anticancer nicotinamide phosphoribosyltransferase inhibitor FK866 in resistant human colorectal cancer cells

Cancer cells' resistance to drugs remains an important problem affecting cancer treatment strategies. We previously studied the nicotinamide phosphoribosyltransferase (NAMPT) inhibitor FK866's resistance mechanisms in the human colorectal cancer HCT116 cells. We established an acquired FK866-resistant cell line, HCT116RFK866. In this study, we investigated gene mutations in parental HCT116 and HCT116RFK866 cells using exome sequencing technology. The results indicated cluster genes related to NAD+ biosynthesis (including NAMPT), DNA repair, and ATP-binding cassette transporters were differentially altered in these cells. Interestingly, HCT116RFK866 cells, which are resistant to other class NAMPT inhibitors, were more sensitive to the anticancer 5-fluorouracil and cisplatin and γ-ray irradiation compared to parental HCT116 cells. This higher sensitivity appears to cause a genetic change in the identified gene clusters by resistance to the NAMPT inhibitor FK866. Collectively, these novel findings provide a better understanding of anticancer candidate NAMPT inhibitors with regard to resistance mechanisms and cancer chemotherapy strategies.

B24N24 fullerene as a carrier for 5-fluorouracil anti-cancer drug delivery: DFT studies

It has been previously indicated that BN nanostructures may be nontoxic and biocompatible. Here the potential application of a B24N24 is explored as a drug delivery system for anti-cancer 5-fluorouracil based on the density functional theory. This drug prefers to attach via its oxygen atoms to the B atoms of the cluster with adsorption energy about −11.90kcalmol−1 based on the dispersion corrected B3LYP level of theory. To make the cluster more appropriate for drug delivery, we replaced a B atom by Si or Al atom to improve the interaction strength. The calculated adsorption energies are about −50.13 and −34.19kcalmol−1 for Al and Si doped BN clusters, respectively. It was found that, in addition to the more negative adsorption energy, the electronic properties of Al-doped BN are significantly sensitive to the drug adsorption. Also, a drug release mechanism is proposed, indicating that in the low pH of the cancer cells the drug and BN cluster are considerably protonated, thereby separating the drug from the surface of the cluster.

A Density Functional Theory Study on the Interaction Between 5-Fluorouracil Drug and C24 Fullerene

Penetration of most of the polar drugs through the cell membrane is a challenging problem. It has been indicated that carbonaceous nanostructures can penetrate into biological cells. Here, we investigated the potential application of a C24 fullerene as a carrier for anti-cancer 5-fluorouracil (5-FU) drug using density functional theory calculations. It was found that the 5-FU interaction with the pristine fullerene is very weak with adsorption energy of about −3.2 kcal/mol which is not suitable for drug delivery. To overcome this problem, one carbon atom is substituted by a boron atom which increases the adsorption energy to −27.2 kcal/mol. The B-doping makes the electronic properties of the fullerene sensitive to the drug. Finally, we proposed a drug release based on the low pH in the cancer cells. It was indicated that attacking protons to the interaction area between the drug and fullerene separates the drug from the carrier.

Stoichiometric molecularly imprinted polymers for the recognition of anti-cancer pro-drug tegafur.

Molecularly imprinted polymers (MIPs) targeting tegafur, an anti-cancer 5-fluorouracil pro-drug, have been prepared by stoichiometric imprinting using 2,6-bis(acrylamido)pyridine (BAAPy) as the functional monomer. Solution association between tegafur and BAAPy was studied by (1)H NMR titration, which confirmed the formation of 1:1 complexes with an affinity constant of 574±15M(-1) in CDCl3. Evaluation of the synthesised materials by HPLC and equilibrium rebinding experiments revealed high selectivity of the imprinted polymer for the pro-drug vs. 5-fluorouracil and other competing analytes, with maximum imprinting factors of 25.3 and a binding capacity of 45.1μmolg(-1). The synthesised imprinted polymer was employed in solid-phase extraction of the pro-drug using an optimised protocol that included a simple wash with the porogen used in the preparation of the material. Tegafur recoveries of up to 96% were achieved from aqueous samples and 92% from urine samples spiked with the template and three competing analytes. The results demonstrate the potential of the prepared polymers in the pre-concentration of tegafur from biological samples, which could be an invaluable tool in the monitoring of patient compliance and drug uptake and excretion.

Surface-Transfer Mass Spectrometry Imaging on a Monoisotopic Silver Nanoparticle Enhanced Target

A new method for both high-resolution laser desorption/ionization mass spectrometry and mass spectrometry imaging is described. The method could be considered as matrix-less because no additional matrix is needed for MS measurements and also because of surface-assisted laser desorption/ionization due to the nanoparticle-rich surface. The standard matrix-assisted laser desorption/ionization target containing unique monoisotopic cationic (109)Ag nanoparticles ((109)AgNPs) was used for high-resolution mass spectrometry imaging of fingermarks and also plant flower and plant stem cross sections with high mass accuracy. The methodology presented in this work allowed visualization of two drugs--anti-inflammatory ibuprofen and anticancer 5-fluorouracil--along with many other compounds found on the finger. Moreover, visualization of herbicide localization inside of the plant stem is also shown. The simple inorganic ions ionized by silver nanoparticles were also found and may be used for their localization in biological material. In addition, the methodology presented here does not require freezing of species or slice-making equipment.

Injectable intratumoral hydrogel as 5-fluorouracil drug depot

The effectiveness of systemically administered anticancer treatments is limited by difficulties in achieving therapeutic doses within tumors, a problem that is complicated by dose-limiting side effects to normal tissue. To increase the efficacy and reduce the toxicity of systemically administered anticancer 5-fluorouracil (5-Fu) treatments in patients, intratumoral administration of an injectable hydrogel has been evaluated in the current work. The MPEG-b-(PCL-ran-PLLA) diblock copolymer (MCL) containing 5-Fu existed in an emulsion-sol state at room temperature and rapidly gelled in vivo at the body temperature. MCL acted as in vivo biodegradable drug depot over a defined experimental period. A single injection of 5-Fu-loaded MCL solution resulted in significant suppression of tumor growth, compared with repeated injection of free 5-Fu as well as saline and MCL alone. For both repeated injections of free 5-Fu and single injection of 5-Fu-loaded MCL, most of the 5-Fu was found in the tumor, indicating the maintenance of therapeutic concentrations of 5-Fu within the target tumor tissue and the prevention of systemic toxicity associated with 5-Fu in healthy normal tissues. In conclusion, this work demonstrated that intratumoral injection of 5-Fu-loaded MCL may induce significant suppression of tumor growth through effective accumulation of 5-Fu in the tumor.

Chiral Nanoporous Metal‐Organic Frameworks with High Porosity as Materials for Drug Delivery

A chiral nanoporous metal-organic framework (MOF) with high porosity is obtained based on nontoxic zinc and achiral hexadentate ligand. It shows high drug loading and slow release of the proportion of the loaded drug with a complete delivery time of about one week when used as a material for adsorption and delivery of anticancer 5-fluorouracil.

Lack of interaction between bropirimine and 5-fluorouracil on human dihydropyrimidine dehydrogenase

1. Bropirimine (2-amino-5-bromo-6-phenyl-4-pyrimidinone) is a member of a class of antineoplastic agents that are administered concomitantly or sequentially with anticancer 5-fluorouracil (5-FU) prodrugs in clinical patients. Interactions between bropirimine and 5-fluorouracil (5-FU) were investigated on dihydropyrimidine dehydrogenase (DPD) activity, the rate-limiting enzyme of 5-FU metabolism, in human liver cytosol. Apparent DPD activity was determined by measuring the recovery of [14C]5-FU by HPLC.2. The apparent activity of 5-FU metabolism (2.1 - 100 μm) showed a linear relationship in the Eadie-Hofstee plot in the pooled cytosol, suggesting that a single enzyme is responsible for apparent 5-FU metabolism. Km and Vmax were estimated to be 23 μm and 0.32 nmol min−1 mg−1 protein, respectively. Apparent DPD activity for 5-FU (25 μm) in the cytosol from 12 individual donors ranged from 0.017 to 0.39 (0.16 ± 0.12) nmol min−1 mg−1 protein, indicating a large intersubject variance.3. The suicidal inactivators of the DPD enzyme, (E)-5-(2-bromovinyl)uracil and 5- bromouracil (6.3 - 50 μm), illustrated concentration-dependent inhibition on DPD activity. Isocytosine (6.3 - 100 μm), used as a negative control, did not affect DPD activity. Bropirimine (6.3 - 100 μm) also did not show any inhibition of DPD activity. Therefore, bropirimine is unlikely to cause increases in 5-FU levels in clinical patients after coadministration of bropirimine with 5-FU prodrugs.