Anticancer Drug Gemcitabine Research Articles

Synergistic effect of Gemcitabin-loaded metal organic frameworks nanoparticles with particle therapy

Combination of nanoagents with radiations has opened up new perspectives in cancer treatment, improving both tumor diagnosis and therapeutic index. This work presents the first investigation of an innovative strategy that combines porous metal–organic frameworks (nanoMOFs) loaded with the anti-cancer drug Gemcitabine monophosphate (GemMP) and particle therapy-a globally emerging technique that offers more precise radiation targeting and enhanced biological efficacy compared to conventional radiotherapy. This radiochemotherapy has been confronted with two major obstacles limiting the efficacy of therapeutics when tested in vivo: (i) the presence of hypoxia, one of the most important causes for radiotherapy failure and (ii) the presence of a microenvironment, main biological barrier to the direct penetration of nanoparticles into cancer cells.On the one hand, this study explore the effects of hypoxia on drug delivery systems in combination with radiation, demonstrating that GemMP-loaded nanoMOFs significantly enhance the anticancer efficacy of particle therapy under both normoxic (pO2 = 20 %) and hypoxic (pO2 = 0.5 %) conditions. Notably, the presence of GemMP-loaded nanoMOFs allows the irradiation dose to be reduced by 1.4-fold in normoxia and at least 1.6-fold in hypoxia, achieving the same cytotoxic effect (SF=10 %) as carbon or helium ions alone. Synergistic effects between GemMP-loaded nanoMOFs and radiations have been observed and quantified. On the other hand, we also highlighted the ability of the nanoMOFs to diffuse through an extracellular matrix and accumulate in cells. An higher effect of the encapsulated GemMP than the free drug was observed, confirming the key role of the nanoMOFs in transporting the active substance to the cancer cells as a Trojan horse. This paves the way to the design of “all-in-one” nanodrugs where each component plays a role in the optimization of cancer therapy to maximize cytotoxic effects on hypoxic tumor cells while minimizing toxicity on healthy tissue.

Radiosensitizer-based injectable hydrogel for enhanced radio-chemotherapy of TNBC

Radionuclide therapy (RNT) stands out as a highly effective method for treating solid tumors. However, its therapeutic efficiency faces challenges due to the radioresistance of tumors, the limited penetration depth and intracellular deposition of rays in tumor tissue, which causes residue of living cancer cells. Herein, we report a novel approach by utilizing radionuclide 131I-labelled polydopamine encapsulated gold nanoparticle co-loaded with the classical anticancer drug gemcitabine within a hydrogel formed from oxidized glucan and chitosan hydrochloride, combining RNT with chemotherapy for cancer treatment. Au, as a high Z element, is able to interact with short-range β-rays to emit bremsstrahlung and secondary charged particles which in turn increase the dose deposited in tumor cells. Simultaneously, gemcitabine is able to affect cell cycle redistribution, resulting in an increase in the radiosensitive cellular component of the cycle, and gemcitabine also inhibits the repair of radioactive damage to cellular DNA, which has a radiosensitizing effect. In both in vivo and vitro experiments, the injectable hydrogel demonstrates excellent biosecurity, stability in radionuclide labeling, and capabilities for single-photon emission computed tomography (SPECT) imaging. Compared analysis with single RNT revealed that combination therapy markedly inhibits the growth of triple-negative breast cancer. This integrated therapeutic strategy establishes an efficient tumor synergistic treatment platform, offering new avenues for advancing radionuclide therapy in the clinical treatment of cancer.

In vitro evolution and whole genome analysis to study chemotherapy drug resistance in haploid human cells

In vitro evolution and whole genome analysis has proven to be a powerful method for studying the mechanism of action of small molecules in many haploid microbes but has generally not been applied to human cell lines in part because their diploid state complicates the identification of variants that confer drug resistance. To determine if haploid human cells could be used in MOA studies, we evolved resistance to five different anticancer drugs (doxorubicin, gemcitabine, etoposide, topotecan, and paclitaxel) using a near-haploid cell line (HAP1) and then analyzed the genomes of the drug resistant clones, developing a bioinformatic pipeline that involved filtering for high frequency alleles predicted to change protein sequence, or alleles which appeared in the same gene for multiple independent selections with the same compound. Applying the filter to sequences from 28 drug resistant clones identified a set of 21 genes which was strongly enriched for known resistance genes or known drug targets (TOP1, TOP2A, DCK, WDR33, SLCO3A1). In addition, some lines carried structural variants that encompassed additional known resistance genes (ABCB1, WWOX and RRM1). Gene expression knockdown and knockout experiments of 10 validation targets showed a high degree of specificity and accuracy in our calls and demonstrates that the same drug resistance mechanisms found in diverse clinical samples can be evolved, discovered and studied in an isogenic background.

Thermosensitive polymer prodrug nanoparticles prepared by an all-aqueous nanoprecipitation process and application to combination therapy

Despite their great versatility and ease of functionalization, most polymer-based nanocarriers intended for use in drug delivery often face serious limitations that can prevent their clinical translation, such as uncontrolled drug release and off-target toxicity, which mainly originate from the burst release phenomenon. In addition, residual solvents from the formulation process can induce toxicity, alter the physico-chemical and biological properties and can strongly impair further pharmaceutical development. To address these issues, we report polymer prodrug nanoparticles, which are prepared without organic solvents via an all-aqueous formulation process, and provide sustained drug release. This was achieved by the “drug-initiated” synthesis of well-defined copolymer prodrugs exhibiting a lower critical solution temperature (LCST) and based on the anticancer drug gemcitabine (Gem). After screening for different structural parameters, prodrugs based on amphiphilic diblock copolymers were formulated into stable nanoparticles by all-aqueous nanoprecipitation, with rather narrow particle size distribution and average diameters in the 50–80 nm range. They exhibited sustained Gem release in human serum and acetate buffer, rapid cellular uptake and significant cytotoxicity on A549 and Mia PaCa-2 cancer cells. We also demonstrated the versatility of this approach by formulating Gem-based polymer prodrug nanoparticles loaded with doxorubicin (Dox) for combination therapy. The dual-drug nanoparticles exhibited sustained release of Gem in human serum and acidic release of Dox under accelerated pathophysiological conditions. Importantly, they also induced a synergistic effect on triple-negative breast cancer line MDA-MB-231, which is a relevant cell line to this combination.

Characterization of Chemical Interactions between Clinical Drugs and the Oral Bacterium, Corynebacterium matruchotii, via Bioactivity-HiTES.

In the field of natural product research, the rediscovery of already-known compounds is one of the significant issues hindering new drug development. Recently, an innovative approach called bioactivity-HiTES has been developed to overcome this limitation, and several new bioactive metabolites have been successfully characterized by this method. In this study, we applied bioactivity-HiTES to Corynebacterium matruchotii, the human oral bacterium, with 3120 clinical drugs as potential elicitors. As a result, we identified two cryptic metabolites, methylindole-3-acetate (MIAA) and indole-3-acetic acid (IAA), elicited by imidafenacin, a urinary antispasmodic drug approved by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). MIAA showed weak antibacterial activity against a pulmonary disease-causing Mycobacterium conceptionense with an IC50 value of 185.7 μM. Unexpectedly, we also found that C. matruchotii metabolized fludarabine phosphate, a USFDA-approved anticancer drug, to 2-fluoroadenine which displayed moderate antibacterial activity against both Bacillus subtilis and Escherichia coli, with IC50 values of 8.9 and 20.1 μM, respectively. Finally, acelarin, a prodrug of the anticancer drug gemcitabine, was found to exhibit unreported antibacterial activity against B. subtilis with an IC50 value of 33.6 μM through the bioactivity-HiTES method as well. These results indicate that bioactivity-HiTES can also be applied to discover biotransformed products in addition to finding cryptic metabolites in microbes.

Oxaliplatin(IV) Prodrugs Functionalized with Gemcitabine and Capecitabine Induce Blockage of Colorectal Cancer Cell Growth-An Investigation of the Activation Mechanism and Their Nanoformulation.

The use of platinum-based anticancer drugs, such as cisplatin, oxaliplatin, and carboplatin, is a common frontline option in cancer management, but they have debilitating side effects and can lead to drug resistance. Combination therapy with other chemotherapeutic agents, such as capecitabine and gemcitabine, has been explored. One approach to overcome these limitations is the modification of traditional Pt(II) drugs to obtain new molecules with an improved pharmacological profile, such as Pt(IV) prodrugs. The design, synthesis, and characterization of two novel Pt(IV) prodrugs based on oxaliplatin bearing the anticancer drugs gemcitabine or capecitabine in the axial positions have been reported. These complexes were able to dissociate into their constituents to promote cell death and induce apoptosis and cell cycle blockade in a representative colorectal cancer cell model. Specifically, the complex bearing gemcitabine resulted in being the most active on the HCT116 colorectal cancer cell line with an IC50 value of 0.49 ± 0.04. A pilot study on the encapsulation of these complexes in biocompatible PLGA-PEG nanoparticles is also included to confirm the retention of the pharmacological properties and cellular drug uptake, opening up to the possible delivery of the studied complexes through their nanoformulation.

Ionophore-Based Polymeric Sensors for Potentiometric Assay of the Anticancer Drug Gemcitabine in Pharmaceutical Formulation: A Comparative Study.

Gemcitabine is a chemotherapeutic agent used to treat various malignancies, including breast and bladder cancer. In the current study, three innovative selective gemcitabine hydrochloride sensors are developed using 4-tert-butylcalix-[8]-arene (sensor 1), β-cyclodextrin (sensor 2), and γ-cyclodextrin (sensor 3) as ionophores. The three sensors were prepared by incorporating the ionophores with o-nitrophenyl octyl ether as plasticizer and potassium tetrakis(4-chlorophenyl) borate as ionic additive into a polyvinyl chloride polymer matrix. These sensors are considered environmentally friendly systems in the analytical research. The linear responses of gemcitabine hydrochloride were in the concentration range of 6.0 × 10-6 to 1.0 × 10-2 mol L-1 and 9.0 × 10-6 to 1.0 × 10-2 mol L-1 and 8.0 × 10-6 to 1.0 × 10-2 mol L-1 for sensors 1, 2, and 3, respectively. Over the pH range of 6-9, fast-Nernst slopes of 52 ± 0.6, 56 ± 0.3, and 55 ± 0.8 mV/decade were found in the same order with correlation regressions of 0.998, 0.999, and 0.998, respectively. The lower limits of detection for the prepared sensors were 2.5 × 10-6, 2.2 × 10-6, and 2.7 × 10-6 mol L-1. The sensors showed high selectivity and sensitivity for gemcitabine. Validation of the sensors was carried out in accordance with the requirements established by the IUPAC, while being inexpensive and easy to use in drug formulation. A statistical analysis of the methods in comparison with the official method showed that there was no significant difference in accuracy or precision between them. It was shown that the new sensors could selectively and accurately find gemcitabine hydrochloride in bulk powder, pharmaceutical formulations, and quality control tests. The ionophore-based sensor shows several advantages over conventional PVC membrane sensor sensors regrading the lower limit of detection, and higher selectivity towards the target ion.

A Sensitive Electrochemical DNA Biosensor for Determination of Anti-Cancer Drug Gemcitabine Based on an AuNPs/MWCNTs/Carbon Paste Electrode

GMB is a common anticancer drug that needs careful monitoring because of its variable and toxic effects. Detecting GMB in biological samples can help adjust the dosage and enhance the treatment outcomes. In this study, a novel electrochemical sensor was developed based on a carbon paste electrode modified with single stranded DNA, gold nanoparticles and multi-walled carbon nanotubes. We characterized the unmodified (bare CPE) and modified (ss-DNA/AuNPs/MWCNTs/CPE) electrodes using scanning electron microscopy (SEM), EDX analysis and cyclic voltammetry (CV) techniques. The oxidation peak current was linearly proportional to the GMB concentration in two linear ranges: 1–10 μM and 10–50 μM, with a detection limit of 0.52 μM and a limit of quantification (LOQ) of 1.75 μM. The lower linear concentration range (1–10 μM) showed a sensitivity of 5.68 A.M−1.cm−2, while the higher range (10–50 μM) showed a sensitivity of 1.34 A.M−1.cm−2. We also investigated the repeatability, applicability and reproducibility of this method for human serum samples. We tested the selectivity and practical ability of the ss-DNA/AuNPs/MWCNTs/CPE for the determination of GMB in the presence of various interfering species and human serum samples. The results indicated that the ss-DNA/AuNPs/MWCNTs/CPE was a selective, reliable and accurate electrochemical sensor for GMB.

Synergic fabrication of arsenic and anticancer drug-loaded ZIF-8 nanocomposites for improved radiofrequency ablation of liver metastasis cancer therapy

ABSTRACT Clinical treatment of hepatocellular carcinoma (HCC) is notoriously tricky because radiofrequency ablation (RFA) might encourage metastasis of remaining HCC. . The therapeutic efficacy of arsenic (A) and promising anticancer drug gemcitabine (G)-loaded zeolitic imidazolate framework-8 nanocomposites (AG@ZIF-8 NCs) on tumour remnants wasinvestigated. Results demonstrated that RFA significantly increased proliferation, induced metastasis, and triggered angiogenesis in recurrent tumours. We show that significant angiogenesis following RFA can increase the enhanced permeability and retention (EPR) effects and emphasize ZIF-8 carriers in recurrent tumours. e effectively fabricated biocompatible AG@ZIF-8 NCs. And they were superior to free gemcitabine in inhibiting cell proliferations, inducing apoptosis, blocking cell invasion and migration, and reversing in vitro EMT following sublethal heat treatment. In addition, AG@ZIF-8 NCs showed significantly improved therapeutic efficiency by reducing residual tumour development and in vivo metastasis compared to free gemcitabine. This study establishes a new standard for managing HCC that persists after RFA.

Anticancer effect of umbelliferone on MKN-45 and MIA PaCa-2 cell lines

In this study, the anticancer activity of umbelliferone (7-hydroxycoumarin-UMB) was investigated in MKN-45 human gastric cancer and MIA PaCa-2 human pancreatic cancer cells. The cytotoxic effect of UMB on MKN-45 and MIA PaCa-2 cells was determined by WST-8 cell viability assay; the effect on colony formation and migration potential by colony forming assay and wound healing/cell migration assay. Apoptotic effect of UMB was determined by measuring the change in mitochondrial membrane potentials, reactive oxygen species levels, and Caspase-3 activities in cells. Anticancer drugs cisplatin and gemcitabine were used as positive controls in experiments, and NIH/Swiss 3 T3 mouse embryonic fibroblast cells were used as a healthy cell group.The results of this study showed that umbelliferone had a significant cytotoxic effect in MKN-45 and MIA PaCa-2 cells, especially after 72 h treatment, while its cytotoxic effect in NIH/3 T3 cells was low. Furthermore, UMB reduces significantly the potential of cells to colonize and migrate; it has been determined that it causes apoptosis by decreasing the mitochondrial membrane potential, increasing intracellular ROS levels and Caspase-3 activity. UMB was found to have more anticancer effect on MIA PaCa-2 cells compared to MKN-45 cells. This showed that UMB has a cell-selective effect.

Pd doped carbon nanotubes as a drug carrier for Gemcitabine anticancer drug: DFT studies

A calculation based on density functional theory has been used to study the ability of Pd doped armchair single-walled armchair carbon nanotubes as a drug delivery system for Gemcitabine anticancer drug. For this purpose, the geometry, reactivity descriptors, energy surface of electrostatic potential, and electronic densities of state were calculated by density functional theory for the Pd/SWCNT in the free mode and interacted with Gemcitabine anticancer drug. The negative binding energy means that the anticancer drug Gemcitabine binds well to the functionalized nanotube, and the presence of active sites help to ceate hydrogen bonds supports the drug bind better to the sidewall of the nanotube. Based on the results, we believe that Pd/SWCNT is a good suggestion as a drug delivery system for Gemcitabine anticancer.

Anti-inflammatory and Protective Effects of Melatonin on Rats Exposed to Anticancer Drugs

ABSTRACT This study was aimed to investigate the effects of Melatonin at )10mg/kg) on liver function enzymes AST,ALT,ALP activity and determination the inflammatory marker CRP activity and total counting of WBC on rats exposed to anticancer drugs Gemcitabine, and protective effects of melatonin in the liver tissue.Materials and Methods: sixty four adult male albino rats were used in this study, weighing (250-350) gm at temperature 22±20C , The animals were feeding and drinking water as needed . the animals were divided into 5 main groups as follow : Group A( Control group n=8 ) given a daily D.W. Group B:(melatonin group n=8)given a daily melatonin 10mg/kg/orally. Group C (Gemcitabine n=16) this group was divided into two group according to Gemcitabine dose (25 and 50 mg/kg). Group D (protective group n=16): this group was divided into two group according to Gemcitabine dose (25 and 50 mg/kg ) together with given a daily melatonin in dose (10mg /kg) orally.Group E (protective and treatment group n=16) : this group was divided into two group according to Gemcitabine dose (25 and 50 mg/kg ). This group was given a daily melatonin in dose (10mg /kg) orally as a treatment. The results showed that melatonin reduced the activity of AST, ALT enzymes compare with gemcitabine treated groups, While increased the activity of ALP in A, B groups compare with gemcitabine treated groups , that induced by chemotherapy drug ,While decreased the activity of CRP inflammatory marker in A, B groups compare with another groups that treated with anticancer drug. Melatonin given protective effect on liver enzymes and tissues from damaged that happened by Gemcitabine in two different dose (25,50 mg/kg ) .

Combination effects of amino acid transporter LAT1 inhibitor nanvuranlat and cytotoxic anticancer drug gemcitabine on pancreatic and biliary tract cancer cells

BackgroundCytotoxic anticancer drugs widely used in cancer chemotherapy have some limitations, such as the development of side effects and drug resistance. Furthermore, monotherapy is often less effective against heterogeneous cancer tissues. Combination therapies of cytotoxic anticancer drugs with molecularly targeted drugs have been pursued to solve such fundamental problems. Nanvuranlat (JPH203 or KYT-0353), an inhibitor for L-type amino acid transporter 1 (LAT1; SLC7A5), has novel mechanisms of action to suppress the cancer cell proliferation and tumor growth by inhibiting the transport of large neutral amino acids into cancer cells. This study investigated the potential of the combined use of nanvuranlat and cytotoxic anticancer drugs.MethodsThe combination effects of cytotoxic anticancer drugs and nanvuranlat on cell growth were examined by a water-soluble tetrazolium salt assay in two-dimensional cultures of pancreatic and biliary tract cancer cell lines. To elucidate the pharmacological mechanisms underlying the combination of gemcitabine and nanvuranlat, we investigated apoptotic cell death and cell cycle by flow cytometry. The phosphorylation levels of amino acid-related signaling pathways were analyzed by Western blot. Furthermore, growth inhibition was examined in cancer cell spheroids.ResultsAll the tested seven types of cytotoxic anticancer drugs combined with nanvuranlat significantly inhibited the cell growth of pancreatic cancer MIA PaCa-2 cells compared to their single treatment. Among them, the combined effects of gemcitabine and nanvuranlat were relatively high and confirmed in multiple pancreatic and biliary tract cell lines in two-dimensional cultures. The growth inhibitory effects were suggested to be additive but not synergistic under the tested conditions. Gemcitabine generally induced cell cycle arrest at the S phase and apoptotic cell death, while nanvuranlat induced cell cycle arrest at the G0/G1 phase and affected amino acid-related mTORC1 and GAAC signaling pathways. In combination, each anticancer drug basically exerted its own pharmacological activities, although gemcitabine more strongly influenced the cell cycle than nanvuranlat. The combination effects of growth inhibition were also verified in cancer cell spheroids.ConclusionsOur study demonstrates the potential of first-in-class LAT1 inhibitor nanvuranlat as a concomitant drug with cytotoxic anticancer drugs, especially gemcitabine, on pancreatic and biliary tract cancers.

Potential of bacteriophage therapy in managing Staphylococcus aureus infections during chemotherapy for lung cancer patients

Respiratory Staphylococcus aureus infection represents a common complication in lung cancer patients, which is characterized with progressively and recurrently intratumor invasion. Although bacteriophages are widely reported as an effective bioweapon for managing bacterial infections, its applicability in handling infectious complications during cancer chemotherapy remains unknown. In this work, we hypothesized cancer chemotherapeutics would influence the efficacy of bacteriophages. To verify this end, interactions between four anticancer drugs (Gemcitabine, Doxorubicin, Cisplatin, and Irinotecan) with phage K were investigated, where Cisplatin directly reduced phage titers while Gemcitabine and Doxorubicin partially inhibited its propagation. The antibacterial efficacy of drug-phage K combinations was tested in a S. aureus infected cancer cell model. Doxorubicin enhanced the antibacterial capacity of phage K, destroying 22-folds of cell-associated bacteria than that of phage K alone use. Also, S. aureus migration was remarkably reduced by Doxorubicin. Overall, our data suggested that Doxorubicin had synergistic effects with phage K in combating S. aureus intracellular infection and migration. This work may broaden the options of indication for phage clinical transformation and also provide reference for the adjunctive application of chemo drugs in intracellular infection management.

Development and characterization of lung surfactant-coated polymer nanoparticles for pulmonary drug delivery

Lung cancer is often diagnosed at an advanced stage where tumors are usually inoperable and first-line therapies are inefficient and have off-targeted adverse effects, resulting in poor patient survival. Here, we report the development of an inhalable poly lactic-co-glycolic acid polymer-based nanoparticle (PLGA-NP) formulation with a biomimetic Infasurf® lung surfactant (LS) coating, for localized and sustained lung cancer drug delivery. The nanoparticles (188 ± 7 nm) were stable in phosphate buffered saline, serum and Gamble's solution (simulated lung fluid), and demonstrated cytocompatibility up to 1000 μg/mL concentration and dose-dependent uptake by lung cancer cells. The LS coating significantly decreased nanoparticle (NP) uptake by NR8383 alveolar macrophages in vitro compared to uncoated NPs. The coating, however, did not impair NP uptake by A549 lung adenocarcinoma cells. The anti-cancer drug gemcitabine hydrochloride encapsulated in the PLGA core was released in a sustained manner while the paclitaxel loaded in the LS shell demonstrated a rapid or burst release profile over 21 days. The drug-loaded NPs significantly decreased cancer cell survival and colony formation in vitro compared to free drugs and single drug-loaded NPs. In vivo studies confirmed greater retention of LS-coated NPs in the lungs of C57BL/6 WT mice compared to uncoated NPs, at 24 h and 72 h following intranasal administration. The overall results confirm that LS coating is a unique strategy for cloaking polymeric NPs to potentially prevent their rapid lung clearance and facilitate prolonged pulmonary drug delivery.

Concurrent induction of apoptosis and necroptosis inapigenin‑treated malignant mesothelioma cells: Reversal ofWarburg effect through Akt inhibition and p53 upregulation.

A high dependence on aerobic glycolysis, known as the Warburg effect, is one of the metabolic features exhibited by tumor cells. Therefore, targeting glycolysis is becoming a very promising strategy for the development of anticancer drugs. In the present study, it was investigated whether pre‑adaptation of malignant mesothelioma (MM) cells to an acidic environment was associated with a metabolic shift to the Warburg phenotype in energy production, and whether apigenin targets acidosis‑driven metabolic reprogramming. Cell viability, glycolytic activity, Annexin V‑PE binding activity, reactive oxygen species (ROS) levels, mitochondrial membrane potential, ATP content, western blot analysis and spheroid viability were assessed in the present study. MM cells pre‑adapted to lactic acid were resistant to the anticancer drug gemcitabine, increased Akt activation, downregulated p53 expression, and upregulated rate‑limiting enzymes in glucose metabolism compared with their parental cells. Apigenin treatment increased cytotoxicity, Akt inactivation and p53 upregulation. Apigenin also reduced glucose uptake along with downregulation of key regulatory enzymes in glycolysis, increased ROS levels with loss of mitochondrial membrane potential, and downregulated the levels of complexes I, III and IV in the mitochondrial electron transport chain with intracellular ATP depletion, resulting in upregulation of molecules mediating apoptosis and necroptosis. Apigenin‑induced alterations of cellular responses were similar to those of Akt inactivation by Ly294002. Overall, the present results provide mechanistic evidence supporting the anti‑glycolytic and cytotoxic role of apigenin via inhibition of the PI3K/Akt signaling pathway and p53 upregulation.

Preparation of Functional Nanoparticles-Loaded Magnetic Carbon Nanohorn Nanocomposites towards Composite Treatment.

Combination therapy for cancer is expected for the synergetic effect of different treatments, and the development of promising carrier materials is demanded for new therapeutics. In this study, nanocomposites including functional nanoparticles (NPs) such as samarium oxide NP for radiotherapy and gadolinium oxide NP as a magnetic resonance imaging agent were synthesized and chemically combined with iron oxide NP-embedded or carbon dot-coating iron oxide NP-embedded carbon nanohorn carriers, where iron oxide NP is a hyperthermia reagent and carbon dot exerts effects on photodynamic/photothermal treatments. These nanocomposites exerted potential for delivery of anticancer drugs (doxorubicin, gemcitabine, and camptothecin) even after being coated with poly(ethylene glycol). The co-delivery of these anticancer drugs played better drug-release efficacy than the independent drug delivery, and the thermal and photothermal procedures enlarged the drug release. Thus, the prepared nanocomposites can be expected as materials to develop advanced medication for combination treatment.

Electrophysiological evaluation of an anticancer drug gemcitabine on cardiotoxicity revealing down-regulation and modification of the activation gating properties in the human rapid delayed rectifier potassium channel.

Gemcitabine is an antineoplastic drug commonly used in the treatment of several types of cancers including pancreatic cancer and non-small cell lung cancer. Although gemcitabine-induced cardiotoxicity is widely recognized, the exact mechanism of cardiac dysfunction causing arrhythmias remains unclear. The objective of this study was to electrophysiologically evaluate the proarrhythmic cardiotoxicity of gemcitabine focusing on the human rapid delayed rectifier potassium channel, hERG channel. In heterologous hERG expressing HEK293 cells (hERG-HEK cells), hERG channel current (IhERG) was reduced by gemcitabine when applied for 24 h but not immediately after the application. Gemcitabine modified the activation gating properties of the hERG channel toward the hyperpolarization direction, while inactivation, deactivation or reactivation gating properties were unaffected by gemcitabine. When gemcitabine was applied to hERG-HEK cells in combined with tunicamycin, an inhibitor of N-acetylglucosamine phosphotransferase, gemcitabine was unable to reduce IhERG or shift the activation properties toward the hyperpolarization direction. While a mannosidase I inhibitor kifunensine alone reduced IhERG and the reduction was even larger in combined with gemcitabine, kifunensine was without effect on IhERG when hERG-HEK cells were pretreated with gemcitabine for 24 h. In addition, gemcitabine down-regulated fluorescence intensity for hERG potassium channel protein in rat neonatal cardiomyocyte, although hERG mRNA was unchanged. Our results suggest the possible mechanism of arrhythmias caused by gemcitabine revealing a down-regulation of IhERG through the post-translational glycosylation disruption possibly at the early phase of hERG channel glycosylation in the endoplasmic reticulum that alters the electrical excitability of cells.

Small anticancer drug release by light: Photochemical internalization of porphyrin-β-cyclodextrin nanoparticles

Aiming to engineer simple, neutral, strongly amphiphilic photoactive nanoparticles (NPs) to specifically target cancer cell lysosomes for drug transport and light-controlled release, new conjugates of β-cyclodextrin with highly hydrophobic triphenylporphyrin bearing different alkyl chains, were synthesized. Although differently sized, all conjugates self-assemble into ~60 nm NPs in water and display similar photoactivity. The NPs target selectively the lysosomes of breast adenocarcinoma MCF-7 cells, embedding in vesicular membranes, as experiments with model liposomes indicate. Either empty or drug-loaded, the NPs lack dark toxicity for 48 h. They bind with differently structured anticancer drugs tamoxifen and gemcitabine as its N-adamantyl derivative. Red light irradiation of cells incubated with drug-loaded NPs results in major reduction of viability (>85 %) for 48 h displaying significant synergy of photo-chemotoxicity, as opposed to empty NPs, and to loaded non-irradiated NPs, in manifestation of photochemical internalization (PCI). Our approach expands the field of PCI into different small molecule chemotherapeutics.

Characterization of tautomeric forms of anti-cancer drug gemcitabine and their interconversion upon mechano-chemical treatment, using ATR-FTIR spectroscopy and complementary methods

Gemcitabine is a widely used anti-cancer drug of pyrimidine structure, which can exist as a free base molecular form in crystals. Tautomers are structural isomers of molecules, which interconvert via proton transfer. Mechano-chemistry studies reactions of solids under mechanical impact. We investigated gemcitabine free base for the presence of specific molecular tautomers, using ATR-FTIR spectroscopic analysis, powder XRD, optical microscopy and HPLC. The amino-keto tautomer has the characteristic infrared (IR) peak of the amino group at 3390 cm−1. For the first time, the imino-keto tautomer of gemcitabine free base was detected. The imino-keto tautomer has the characteristic IR peak of the =N–H group, and its peak due to the CO group in pyrimidine ring is shifted vs. that of the amino-keto tautomer. This serves as the unique spectroscopic “fingerprints” of these tautomers. The ATR-FTIR spectroscopic analysis shows that gemcitabine free base can be enriched with the amino-keto or the imino-keto tautomer. Further, we studied the transformation of gemcitabine free base in crystals between its tautomers under conditions of liquid-assisted grinding (LAG). The imino-keto tautomer undergoes tautomerization to the amino-keto tautomer, while the amino-keto tautomer remains stable. No destruction of molecules of gemcitabine free base, when present as either tautomer, occurs during LAG as was verified by the HPLC-UV analysis. LAG is a new, straightforward, facile and fast method to interconvert tautomers in crystals, and ATR-FTIR spectroscopy is a method of choice to study tautomerization reactions of pharmaceuticals. The presented approach is promising for analysis of crystals of drugs containing one or more than one tautomer, and the knowledge-driven design of composite materials, which contain specific tautomeric molecular forms of pyrimidines, purines and other biologically active heterocyclic compounds.