ABSTRACT
Background: Current immunotherapies with unexpected severe side effects and treatment resistance have not resulted in the desired outcomes for patients with melanoma, and there is a need to discover more effective medications. Cytotoxin (CTX) from Cobra Venom has been established to have favorable cytolytic activity and antitumor efficacy and is regarded as a promising novel anticancer agent. However, amphiphilic CTX with excellent anionic phosphatidylserine lipid-binding ability may also damage normal cells. Methods: We developed pH-responsive liposomes with a high CTX load (CTX@PSL) for targeted acidic-stimuli release of drugs in the tumor microenvironment. The morphology, size, zeta potential, drug-release kinetics, and preservation stability were characterized. Cell uptake, apoptosis-promoting effects, and cytotoxicity were assessed using MTT assay and flow cytometry. Finally, the tissue distribution and antitumor effects of CTX@PSL were systematically assessed using an in vivo imaging system. Results: CTX@PSL exhibited high drug entrapment efficiency, drug loading, stability, and a rapid release profile under acidic conditions. These nanoparticles, irregularly spherical in shape and small in size, can effectively accumulate at tumor sites (six times higher than free CTX) and are rapidly internalized into cancer cells (2.5-fold higher cell uptake efficiency). CTX@PSL displayed significantly stronger cytotoxicity (IC50 0.25 µg/mL) and increased apoptosis in than the other formulations (apoptosis rate 71.78±1.70%). CTX@PSL showed considerably better tumor inhibition efficacy than free CTX or conventional liposomes (tumor inhibition rate 79.78±5.93%). Conclusion: Our results suggest that CTX@PSL improves tumor-site accumulation and intracellular uptake for sustained and targeted CTX release. By combining the advantages of CTX and stimuli-responsive nanotechnology, the novel CTX@PSL nanoformulation is a promising therapeutic candidate for cancer treatment.
Subject(s)
Antineoplastic Agents , Elapid Venoms , Liposomes , Liposomes/chemistry , Hydrogen-Ion Concentration , Animals , Elapid Venoms/chemistry , Elapid Venoms/pharmacology , Humans , Cell Line, Tumor , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Mice , Apoptosis/drug effects , Drug Liberation , Cytotoxins/chemistry , Cytotoxins/pharmacology , Cytotoxins/pharmacokinetics , Drug Delivery Systems/methods , Tissue Distribution , Tumor Microenvironment/drug effects , Nanoparticles/chemistryABSTRACT
Purpose: The study aimed to address the non-specific toxicity of cytotoxins (CTX) in liver cancer treatment and explore their combined application with the photosensitizer Ce6, co-loaded into carbonized Zn/Co bimetallic organic frameworks. The goal was to achieve controlled CTX release and synergistic photodynamic therapy, with a focus on evaluating anti-tumor activity against human liver cancer cell lines (Hep G2). Methods: Purified cobra cytotoxin (CTX) and photosensitizer Ce6 were co-loaded into carbonized Zn/Co bimetallic organic frameworks, resulting in RGD-PDA@C-ZIF@(CTX+Ce6). The formulation was designed with surface-functionalization using polydopamine and tumor-penetrating peptide RGD. This approach aimed to facilitate controlled CTX release and enhance the synergistic effect of photodynamic therapy. The accumulation of RGD-PDA@C-ZIF@(CTX+Ce6) at tumor sites was achieved through RGD's active targeting and the enhanced permeability and retention (EPR) effect. In the acidic tumor microenvironment, the porous structure of the metal-organic framework disintegrated, releasing CTX and Ce6 into tumor cells. Results: Experiments demonstrated that RGD-PDA@C-ZIF@(CTX+Ce6) nanoparticles, combined with near-infrared laser irradiation, exhibited optimal anti-tumor effects against human liver cancer cells. The formulation showcased heightened anti-tumor activity without discernible systemic toxicity. Conclusion: The study underscores the potential of utilizing metal-organic frameworks as an efficient nanoplatform for co-loading cytotoxins and photodynamic therapy in liver cancer treatment. The developed formulation, RGD-PDA@C-ZIF@(CTX+Ce6), offers a promising avenue for advancing the clinical application of cytotoxins in oncology, providing a solid theoretical foundation for future research and development.
Subject(s)
Indoles , Liver Neoplasms , Metal-Organic Frameworks , Photochemotherapy , Photosensitizing Agents , Zinc , Humans , Photochemotherapy/methods , Metal-Organic Frameworks/chemistry , Metal-Organic Frameworks/pharmacology , Liver Neoplasms/drug therapy , Zinc/chemistry , Zinc/pharmacology , Indoles/chemistry , Indoles/pharmacology , Indoles/administration & dosage , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Photosensitizing Agents/administration & dosage , Animals , Hep G2 Cells , Cobalt/chemistry , Cobalt/pharmacology , Oligopeptides/chemistry , Oligopeptides/pharmacology , Oligopeptides/pharmacokinetics , Polymers/chemistry , Mice , Cytotoxins/chemistry , Cytotoxins/pharmacology , Cytotoxins/pharmacokinetics , Mice, Nude , Mice, Inbred BALB C , Cell Survival/drug effectsABSTRACT
Nucleos(t)ide analogues (NA) belong to a family of compounds widely used in anticancer/antiviral treatments. They generally exhibit a cell toxicity limited by cellular uptake levels and the resulting nucleos(t)ides metabolism modifications, interfering with the cell machinery for nucleic acids synthesis. We previously synthesized purine nucleos(t)ide analogues N7-coordinated to a platinum centre with unaltered sugar moieties of the type: [Pt(dien)(N7-dGuo)]2+ (1; dien = diethylenetriamine; dGuo = 2'-deoxy-guanosine), [Pt(dien)(N7-dGMP)] (2; dGMP = 5'-(2'-deoxy)-guanosine monophosphate), and [Pt(dien)(N7-dGTP)]2- (3; dGTP = 5'-(2'-deoxy)-guanosine triphosphate), where the indicated electric charge is calculated at physiological pH (7.4). In this work, we specifically investigated the uptake of these complexes (1-3) at the plasma membrane level. Specific experiments on HeLa cervical cancer cells indicated a relevant cellular uptake of the model platinated deoxynucleos(t)ide 1 and 3 while complex 2 appeared unable to cross the cell plasma membrane. Obtained data buttress an uptake mechanism involving Na+-dependent concentrative transporters localized at the plasma membrane level. Consistently, 1 and 3 showed higher cytotoxicity with respect to complex 2 also suggesting selective possible applications as antiviral/antitumor drugs among the used model compounds.
Subject(s)
Cell Membrane/metabolism , Cytotoxins , Guanosine , Organoplatinum Compounds , Biological Transport , Cytotoxins/chemical synthesis , Cytotoxins/chemistry , Cytotoxins/pharmacokinetics , Cytotoxins/pharmacology , Guanosine/analogs & derivatives , Guanosine/chemistry , Guanosine/pharmacokinetics , Guanosine/pharmacology , HeLa Cells , Humans , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacokinetics , Organoplatinum Compounds/pharmacologyABSTRACT
Antibody-drug conjugates (ADCs) are currently used for the targeted delivery of drugs to diseased cells, but intracellular drug delivery and therefore efficacy may be suboptimal because of the large size, slow internalization and ineffective intracellular trafficking of the antibody. Using a phage display method selecting internalizing phages only, we developed internalizing single domain antibodies (sdAbs) with high binding affinity to rat PDGFRß, a receptor involved in different types of diseases. We demonstrate that these constructs have different characteristics with respect to internalization rates but all traffic to lysosomes. To compare their efficacy in targeted drug delivery, we conjugated the sdAbs to a cytotoxic drug. The conjugates showed improved cytotoxicity correlating to their internalization speed. The efficacy of the conjugates was inhibited in the presence of vacuolin-1, an inhibitor of lysosomal maturation, suggesting lysosomal trafficking is needed for efficient drug release. In conclusion, sdAb constructs with different internalization rates can be designed against the same target, and sdAbs with a high internalization rate induce more cell killing than sdAbs with a lower internalization rate in vitro. Even though the overall efficacy should also be tested in vivo, sdAbs are particularly interesting formats to be explored to obtain different internalization rates.
Subject(s)
Drug Carriers , Receptor, Platelet-Derived Growth Factor beta/antagonists & inhibitors , Single-Chain Antibodies , Animals , Cell Line, Tumor , Cytotoxins/chemistry , Cytotoxins/pharmacokinetics , Cytotoxins/pharmacology , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Drug Carriers/pharmacology , Lysosomes/metabolism , Mice , Proof of Concept Study , Rats , Single-Chain Antibodies/chemistry , Single-Chain Antibodies/pharmacokinetics , Single-Chain Antibodies/pharmacologyABSTRACT
Conjugation of small molecules such as lipids or receptor ligands to anti-cancer drugs has been used to improve their pharmacological properties. In this work, we studied the biological effects of several small-molecule enhancers into a short oligonucleotide made of five floxuridine units. Specifically, we studied adding cholesterol, palmitic acid, polyethyleneglycol (PEG 1000), folic acid and triantennary N-acetylgalactosamine (GalNAc) as potential enhancers of cellular uptake. As expected, all these molecules increased the internalization efficiency with different degrees depending on the cell line. The conjugates showed antiproliferative activity due to their metabolic activation by nuclease degradation generating floxuridine monophosphate. The cytotoxicity and apoptosis assays showed an increase in the anti-cancer activity of the conjugates related to the floxuridine oligomer, but this effect did not correlate with the internalization results. Palmitic and folic acid conjugates provide the highest antiproliferative activity without having the highest internalization results. On the contrary, cholesterol oligomers that were the best-internalized oligomers had poor antiproliferative activity, even worse than the unmodified floxuridine oligomer. Especially relevant is the effect induced by palmitic and folic acid derivatives generating the most active drugs. These results are of special interest for delivering other therapeutic oligonucleotides.
Subject(s)
Apoptosis/drug effects , Cell Proliferation/drug effects , Cytotoxins , Floxuridine , Oligonucleotides , Cytotoxins/chemistry , Cytotoxins/pharmacokinetics , Cytotoxins/pharmacology , Floxuridine/chemistry , Floxuridine/pharmacokinetics , Floxuridine/pharmacology , HeLa Cells , Hep G2 Cells , Humans , Oligonucleotides/chemistry , Oligonucleotides/pharmacokinetics , Oligonucleotides/pharmacologyABSTRACT
BACKGROUND: Inclusion of anticancer drugs into biocompatible nanoparticulate carriers decreases the general toxicity and improves the efficacy of clinical treatments due to the reduction of soluble circulating free drugs. METHODS: In addition, removal of emerging drug contaminants from wastewaters is a necessity that should be seriously attended. Boron nitride (BN) is a choice in drug delivery because of its many surprising properties. Here, boron nitride nanoparticles are prepared, characterized by Fourier-transform infrared spectroscopy (FT-IR) and x-ray diffraction (XRD) and used in the delivery of melphalan anti-cancer drug. RESULTS: Then, density functional theory (DFT) calculations are carried out to study the adsorption of this drug on the surface of pure boron nitride fullerene via familiar hybrid functionals B3LYP and B3PW91. In addition, the polarizable continuum model (PCM) calculations show that BN is stable in water. CONCLUSION: Finally, the in vitro cellular toxicity and viability of BN nanoparticles was examined on ES-2 cancer cells. The inhibitory dose IC50 of the material confirmed acceptable cytotoxicity and nanoparticles affected the average growth of the ES-2 cancer cells.
Subject(s)
Antineoplastic Agents , Boron Compounds , Cytotoxins , Nanostructures , Ovarian Neoplasms , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Boron Compounds/chemistry , Boron Compounds/pharmacokinetics , Boron Compounds/pharmacology , Cell Line, Tumor , Cytotoxins/chemical synthesis , Cytotoxins/chemistry , Cytotoxins/pharmacokinetics , Cytotoxins/pharmacology , Female , Humans , Nanostructures/chemistry , Nanostructures/therapeutic use , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/metabolismABSTRACT
The poor and nonselective penetration of current chemotherapeutics across the plasma membranes of cancer cells, which is necessary for the targeted disruption of the intracellular machinery, remains a major pharmaceutical challenge. In several cell types, including mast cells and macrophages, exposure to extracellular ATP is known to stimulate passive entry of large and otherwise membrane impermeable cationic dyes, which is usually attributed to conduction through ionotropic P2X receptors. Here, we report that elevations in cytosolic Ca2+ stimulate the rapid uptake and nuclear accumulation of a DNA-binding fluorescent cation, Hoechst 33258 (H33258), in cervical cancer cells. The H33258 uptake was dependent on activation of intermediate conductance Ca2+-activated K+ channels (KCa3.1), and direct stimulation of the channel with the activators SKA 31 and DCEBIO was sufficient to induce cellular uptake of H33258 directly. In contrast to the results from cancerous cervical cells, KCa3.1-dependent H33258 uptake was rarely observed in epithelial cells derived from the ectocervix and transformation zone of healthy cervical tissue. Furthermore, whole-cell patch clamp experiments and assessment of membrane potential using the slow voltage-sensitive dye bis-(1,3-diethylthiobarbituric acid)trimethine oxonol revealed a significant difference in functional KCa3.1 activity between cancerous and healthy cervical epithelial cells, which correlated strongly with the incidence of KCa3.1-dependent H33258 uptake. Finally, we show that activation of KCa3.1 channels caused a modest but significant sensitization of cancer cells to the growth suppressant effects of H33258, lending plausibility to the idea of using KCa3.1 channel activators to enhance cell penetration of small cationic toxins into cancer cells expressing these channels.
Subject(s)
Benzimidazoles , Cytotoxins , DNA, Neoplasm/metabolism , Intermediate-Conductance Calcium-Activated Potassium Channels/metabolism , Neoplasm Proteins/metabolism , Uterine Cervical Neoplasms/metabolism , Benzimidazoles/pharmacokinetics , Benzimidazoles/pharmacology , Biological Transport, Active , Cell Line, Tumor , Cytotoxins/pharmacokinetics , Cytotoxins/pharmacology , Female , Humans , Uterine Cervical Neoplasms/pathologyABSTRACT
Novel vitamin E chelate derivatives and their VIV/V complexes have been synthesized and characterized, and their anticancer properties have been evaluated. The new complexes have been designed to exhibit enhanced cytotoxicity by combining high lipophilicity with the properties of vanadium to induce the formation of reactive oxygen species (ROS). In particular, the ß-tocopherol derivatives with iminodiethanol (ß-tocDEA) and dipicolylamine (ß-tocDPA) as well their VV and VIV complexes, [VVO(ß-tocDEA] and [VIVO(ß-tocDPA] have been synthesized and characterized by Nuclear Magnetic Resonance (NMR), Ultra Violet-Visible (UV-Vis) and Electron Paramagnetic Resonance (EPR) spectroscopies. Although the ß-tocopherol compounds exhibit antioxidant activity their complexes induce formation of radicals. In addition, two vanadium amphiphilic complexes of 2,2'-((2-hydroxyoctadecyl)azanediyl)bis(ethan-1-ol) (C18DEA) and 1-(bis(pyridin-2-ylmethyl)amino)octadecan-2-ol (C18DPA) known to activate O2 and produce ROS were synthesized and characterized (C. Drouza, A. Dieronitou, I. Hadjiadamou, M. Stylianou, J. Agric. Food. Chem., vol. 65, 2017, pp. 4942-4951). The four amphiphilic vanadium complexes exhibit enhanced hydrolytic stability. All compounds found to be cytotoxic for cancer cells exhibiting activity similar or higher to cis-platin.
Subject(s)
Coordination Complexes , Cytotoxins , Lipids , Neoplasms , Vanadium , Vitamin E , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Coordination Complexes/pharmacokinetics , Coordination Complexes/pharmacology , Cytotoxins/chemical synthesis , Cytotoxins/chemistry , Cytotoxins/pharmacokinetics , Cytotoxins/pharmacology , HEK293 Cells , HeLa Cells , Humans , Lipids/chemical synthesis , Lipids/chemistry , Lipids/pharmacokinetics , Lipids/pharmacology , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Vanadium/chemistry , Vanadium/pharmacokinetics , Vanadium/pharmacology , Vitamin E/chemical synthesis , Vitamin E/chemistry , Vitamin E/pharmacokinetics , Vitamin E/pharmacologyABSTRACT
Iron(III) and nickel(II) complexes bearing a thiosemicarbazone framework were synthesized by a one-pot synthesis method. The structures were characterized by elemental analysis, IR, 1 H NMR, APCI Mass, conductivity, magnetic moment measurements. Molecular and crystal structures of the iron(III) complex were obtained from single-crystal X-ray diffraction. The findings showed that the metal atom adopts a slightly distorted square-pyramidal coordination, with the four donor atoms of the thiosemicarbazone ligand defining the basal plane and a chloride atom occupying the apical position. In the crystal lattice, the structure is stabilized by intermolecular OâH···O and CâH···O interactions. The cytotoxic activity was studied by MTT assay, the expression levels of cytochrome P450 (CYP) enzymes by Western blot, and the lipophilicity (LogP) by using the shake-flask method, another pharmacokinetic parameter. The findings showed that the IC50 values decreased with the decrease of the LogP values of the substances. Cytochrome P450 expression levels were found specific for each compound and each cell line. As a result, the pharmacokinetic properties of the newly synthesized thiosemicarbazone compounds are crucial for oral administration and provide us with clues for prospective in vivo studies.
Subject(s)
Antineoplastic Agents , Cytotoxins , Thiosemicarbazones , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Caco-2 Cells , Cytotoxins/chemical synthesis , Cytotoxins/chemistry , Cytotoxins/pharmacokinetics , Cytotoxins/pharmacology , Drug Screening Assays, Antitumor , HCT116 Cells , HT29 Cells , Hep G2 Cells , Humans , Thiosemicarbazones/chemical synthesis , Thiosemicarbazones/chemistry , Thiosemicarbazones/pharmacokinetics , Thiosemicarbazones/pharmacologyABSTRACT
Cancer remains one of the deadliest non-infectious diseases of the 21st century, causing millions of mortalities per year worldwide. Analyses of conventional treatments, such as radiotherapy and chemotherapy, have shown not only a lower therapeutic efficiency rate but also plethora of side-effects. Considering the desperate need to identify promising anticancer agents, researchers are in quest to design and develop new tumoricidal drugs from natural sources. Over the past few years, scorpion venoms have shown exemplary roles as pivotal anticancer agents. Scorpion venoms associated metabolites, particularly toxins demonstrated in vitro anticancer attributes against diversified cell lines by inhibiting the growth and progression of the cell cycle, inhibiting metastasis by blocking ion channels such as K+ and Cl- , and/or inducing apoptosis by intrinsic and extrinsic pathways. This review sheds light not only on in vitro anticancer properties of distinct scorpion venoms and their toxins, but also on their mechanism of action for designing and developing new therapeutic drugs in future.
Subject(s)
Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cytotoxins/pharmacokinetics , Cytotoxins/therapeutic use , Neoplasms/drug therapy , Scorpion Venoms/pharmacokinetics , Scorpion Venoms/therapeutic use , Antineoplastic Agents/pharmacokinetics , HumansABSTRACT
Quercetin (Qu) is a natural flavonoid present in many commonly consumed food items. The dietary phytochemical quercetin prevents tumor proliferation and is a potent therapeutic cancer agent. The purpose of this study was to synthesize and characterize quercetin-loaded poly(lactic-co-glycolic acid) nanoparticles (Qu1NP, Qu2NP, and Qu3NP) with different size and encapsulation properties and to evaluate their in vitro activity on C6 glioma cells. Nanoparticles were synthesized by single emulsion solvent evaporation method. Then, particle size, zeta potential, polydispersity index and encapsulation efficiency of nanoparticles were determined. Particle size of Qu1NP, Qu2NP, and Qu3NPs were determined as 215.2 ± 6.2, 282.3 ± 7.9, and 584.5 ± 15.2 nm respectively. Treating C6 glioma cells with all nanoparticle formulations effectively inhibited the cell proliferation. Qu1NPs were showed the lowest IC50 value in 48 h with 29.9 µg/ml and achieved higher cellular uptake among other nanoparticles and Qu. Additionally, 48-h treatment with Qu1NPs significantly decreased MDA level (14.90 nmol/µg protein) on C6 glioma cells which is related to reduced oxidative stress in cells. Findings of this study revealed that quercetin's cellular uptake and anti-oxidant activity is improved by small-sized Qu1NPs in C6 glioma cells.
Subject(s)
Antioxidants/toxicity , Cytotoxins/toxicity , Glioma/metabolism , Nanoparticles/metabolism , Nanoparticles/toxicity , Quercetin/toxicity , Animals , Antioxidants/pharmacokinetics , Cell Line, Tumor , Cell Survival/drug effects , Cell Survival/physiology , Cytotoxins/pharmacokinetics , Glioma/drug therapy , Particle Size , Quercetin/pharmacokinetics , RatsABSTRACT
Aim: A novel folated pluronic F127 (FA-F127) was synthesised, so as to modify liposomes with FA group on the surface, and evaluate the effects of FA-F127 modification on the properties of the modified liposomes.Methods: FA was linked to one end of pluronic F127, via the terminal OH group, to obtain FA-F127 and the structure was characterised. FA-F127 modified curcumin liposomes (cur-FA-F127-Lps) were prepared. The physicochemical characteristics of cur-FA-F127-Lps, including morphology and particle size, were studied. The in vitro cytotoxicity of cur-FA-F127-Lps against KB cancer cells was determined by MTT tests.Results: The effects of FA-F127 modification on the average particle size, PDI, curcumin encapsulation efficiency and microstructure were not significant. Compared with nonfolated F127 liposomes (cur-F127-Lps), cur-FA-F127-Lps exhibited significantly higher cytotoxicity towards KB cells.Conclusions: Folic acid modified liposomes provide a novel strategy to improve the chemotherapeutic efficacy of hydrophobic bioactive compounds.
Subject(s)
Curcumin , Cytotoxins , Neoplasms/drug therapy , Poloxamer , Cell Line, Tumor , Curcumin/chemistry , Curcumin/pharmacokinetics , Curcumin/pharmacology , Cytotoxins/chemistry , Cytotoxins/pharmacokinetics , Cytotoxins/pharmacology , Humans , Liposomes , Neoplasms/metabolism , Neoplasms/pathology , Poloxamer/analogs & derivatives , Poloxamer/chemistry , Poloxamer/pharmacokinetics , Poloxamer/pharmacologyABSTRACT
Semiconductor quantum dots (QDs) are attractive fluorescent contrast agents for in vivo imaging due to their superior photophysical properties, but traditional QDs comprise toxic materials such as cadmium or lead. Copper indium sulfide (CuInS2, CIS) QDs have been posited as a nontoxic and potentially clinically translatable alternative; however, previous in vivo studies utilized particles with a passivating zinc sulfide (ZnS) shell, limiting direct evidence of the biocompatibility of the underlying CIS. For the first time, we assess the biodistribution and toxicity of unshelled CIS and partially zinc-alloyed CISZ QDs in a murine model. We show that bare CIS QDs breakdown quickly, inducing significant toxicity as seen in organ weight, blood chemistry, and histology. CISZ demonstrates significant, but lower, toxicity compared to bare CIS, while our measurements of core/shell CIS/ZnS are consistent with literature reports of general biocompatibility. In vitro cytotoxicity is dose-dependent on the amount of metal released due to particle degradation, linking degradation to toxicity. These results challenge the assumption that removing heavy metals necessarily reduces toxicity: indeed, we find comparable in vitro cytotoxicity between CIS and CdSe QDs, while CIS caused severe toxicity in vivo compared to CdSe. In addition to highlighting the complexity of nanotoxicity and the differences between the in vitro and in vivo outcomes, these unexpected results serve as a reminder of the importance of assessing the biocompatibility of core QDs absent the protective ZnS shell when making specific claims of compositional biocompatibility.
Subject(s)
Copper , Cytotoxins , Indium , Quantum Dots , Sulfides , Animals , Copper/chemistry , Copper/pharmacokinetics , Copper/pharmacology , Cytotoxins/chemistry , Cytotoxins/pharmacokinetics , Cytotoxins/pharmacology , Dose-Response Relationship, Drug , Female , Hep G2 Cells , Humans , Indium/chemistry , Indium/pharmacokinetics , Indium/pharmacology , Mice , Mice, Inbred BALB C , Quantum Dots/chemistry , Quantum Dots/therapeutic use , Sulfides/chemistry , Sulfides/pharmacokinetics , Sulfides/pharmacologyABSTRACT
Convection enhanced delivery is an effective alternative to routine delivery methods to overcome the blood brain barrier. However, its treatment efficacy remains disappointing in clinic owing to the rapid drug elimination in tumour tissue. In this study, multiphysics modelling is employed to investigate the combination delivery of anti-angiogenic and cytotoxic drugs from the perspective of intratumoural transport. Simulations are based on a 3-D realistic brain tumour model that is reconstructed from patient magnetic resonance images. The tumour microvasculature is targeted by bevacizumab, and six cytotoxic drugs are included, as doxorubicin, carmustine, cisplatin, fluorouracil, methotrexate and paclitaxel. The treatment efficacy is evaluated in terms of the distribution volume where the drug concentration is above the corresponding LD90. Results demonstrate that the infusion of bevacizumab can slightly improve interstitial fluid flow, but is significantly efficient in reducing the fluid loss from the blood circulatory system to inhibit the concentration dilution. As the transport of bevacizumab is dominated by convection, its spatial distribution and anti-angiogenic effectiveness present high sensitivity to the directional interstitial fluid flow. Infusing bevacizumab could enhance the delivery outcomes of all the six drugs, however, the degree of enhancement differs. The delivery of doxorubicin can be improved most, whereas, the impacts on methotrexate and paclitaxel are limited. Fluorouracil could cover the comparable distribution volume as paclitaxel in the combination therapy for effective cell killing. Results obtain in this study could be a guide for the design of this co-delivery treatment.
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Brain Neoplasms/drug therapy , Cytotoxins/administration & dosage , Models, Biological , Angiogenesis Inhibitors/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Bevacizumab/administration & dosage , Bevacizumab/pharmacokinetics , Brain Neoplasms/blood supply , Brain Neoplasms/metabolism , Brain Neoplasms/pathology , Carmustine/administration & dosage , Carmustine/pharmacokinetics , Cisplatin/administration & dosage , Cisplatin/pharmacokinetics , Convection , Cytotoxins/pharmacokinetics , Doxorubicin/administration & dosage , Doxorubicin/pharmacokinetics , Fluorouracil/administration & dosage , Fluorouracil/pharmacokinetics , Humans , Methotrexate/administration & dosage , Methotrexate/pharmacokinetics , Microvessels/drug effects , Paclitaxel/administration & dosage , Paclitaxel/pharmacokineticsABSTRACT
Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14-20 mg L-1 ) even after many months of treatment due to low water solubility, bioavailability, and unfavorable pharmacokinetic profile. Here a novel MT nanoformulation with very high MT concentrations in physiological aqueous media is reported. The MT-loaded nanoformulations are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction which confirms the amorphous nature of the drug. The polymer itself does not show any cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI-H295 both in monolayers and tumor cell spheroids, micellar MT is demonstrated to exhibit comparable efficacy to its ethanol solution. It is postulated that this formulation will be suitable for i.v. application and rapid attainment of therapeutic plasma concentrations. In conclusion, the micellar formulation is considered a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity toward ACC in vitro.
Subject(s)
Adrenal Cortex Neoplasms/drug therapy , Adrenocortical Carcinoma/drug therapy , Cytotoxins , Drug Carriers , Micelles , Mitotane , Adrenal Cortex Neoplasms/metabolism , Adrenal Cortex Neoplasms/pathology , Adrenocortical Carcinoma/metabolism , Adrenocortical Carcinoma/pathology , Cytotoxins/chemistry , Cytotoxins/pharmacokinetics , Cytotoxins/pharmacology , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Drug Carriers/pharmacology , Hep G2 Cells , Humans , Mitotane/chemistry , Mitotane/pharmacokinetics , Mitotane/pharmacology , SolubilityABSTRACT
Bacterial toxins have received a great deal of attention in the development of antitumor agents. Currently, these protein toxins were used in the immunotoxins as a cancer therapy strategy. Despite the successful use of immunotoxins, immunotherapy strategies are still expensive and limited to hematologic malignancies. In the current study, for the first time, a nano-toxin comprised of truncated pseudomonas exotoxin (PE38) loaded silver nanoparticles (AgNPs) were prepared and their cytotoxicity effect was investigated on human breast cancer cells. The PE38 protein was cloned into pET28a and expressed in Escherichia coli, BL21 (DE3), and purified using metal affinity chromatography and was analyzed by 15% sodium dodecyl sulfate-polyacrylamide gel electrophoresis. AgNPs were biologically prepared using cell-free supernatant of E. Coli K12 strain. Nanoparticle formation was characterized by energy dispersive spectroscopy, transmission electron microscopy, and dynamic light scattering. The PE38 protein was loaded on AgNPs and prepared the PE38-AgNPs nano-toxin. Additionally, in vitro release indicated a partial slow release of toxin in about 100 hr. The nano-toxin exhibited dose-dependent cytotoxicity on MCF-7 cells. Also, real-time polymerase chain reaction results demonstrated the ability of nano-toxin to upregulate Bax/Bcl-2 ratio and caspase-3, -8, -9, and P53 apoptotic genes in the MCF-7 tumor cells. Apoptosis induction was determined by Annexin-V/propidium flow cytometry and caspases activity assay after treatment of cancer cells with the nano-toxin. In general, in the current study, the nano-toxin exhibit an inhibitory effect on the viability of breast cancer cells through apoptosis, which suggests that AgNPs could be used as a delivery system for targeting of toxins to cancer cells.
Subject(s)
ADP Ribose Transferases/pharmacology , Bacterial Toxins/pharmacology , Breast Neoplasms/drug therapy , Cytotoxins/pharmacokinetics , Exotoxins/pharmacology , Metal Nanoparticles/chemistry , Virulence Factors/pharmacology , ADP Ribose Transferases/chemistry , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Bacterial Toxins/chemistry , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Caspase 3/genetics , Caspases/genetics , Cell Proliferation/drug effects , Cytotoxins/chemistry , Escherichia coli/genetics , Exotoxins/chemistry , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , MCF-7 Cells , Microscopy, Electron, Transmission , Proto-Oncogene Proteins c-bcl-2/genetics , Silver/chemistry , Silver/pharmacology , Virulence Factors/chemistry , bcl-2-Associated X Protein/genetics , Pseudomonas aeruginosa Exotoxin AABSTRACT
BACKGROUND: Bovine viral diarrhoea virus (BVDV), an enveloped, single-stranded, positive-sense RNA virus from the Flaviviridae family, is a globally distributed bovine pathogen. BVDV infection in cattle, despite having a wide range of clinical manifestations, is invariably responsible for significant economic losses. To counteract these losses, various schemes to control and eradicate BVDV have been implemented, although safe drugs effectively inhibiting the replication of the virus are still lacking. The purpose of this study was to characterize the antiviral effect of naturally occurring proteins and peptide, such as bovine lactoferrin, chicken egg lysozyme, and nisin from Lactococcus lactis, used both individually and in combination, against the cytopathic NADL strain of BVDV in vitro. After determining the cytotoxicity level of each protein or peptide to MDBK cells, its antiviral effects were evaluated using virucidal, cytopathic effect inhibition and viral yield reduction assays. In addition, the influence of the tested compounds on the intracellular viral RNA level was determined. RESULTS: The highest efficacy among the single treatments was achieved by bovine lactoferrin, which was effective both at the early stages of viral infection and during its entire course, although the effect weakened over time. Nisin and lysozyme were effective at later stages of infection, and the intensity of their effect did not diminish with time. Nisin+lactoferrin and lysozyme+lactoferrin combinations demonstrated stronger antiviral effects than did the single substances. The nisin+lactoferrin mixture present during the whole period of infection produced the strongest anti-BVDV effect in our entire research on both the extracellular viral titre (titre reduction up to 2.875 log ≈ 99.9%) and the intracellular viral RNA level (reduction up to 89%), and this effect intensified over the incubation time. CONCLUSIONS: The tested substances could be applied in bovine viral diarrhoea prevention and therapy, especially when used in combination.
Subject(s)
Antiviral Agents/pharmacology , Diarrhea Viruses, Bovine Viral/drug effects , Lactoferrin/pharmacology , Muramidase/pharmacology , Nisin/pharmacology , Animals , Antiviral Agents/toxicity , Cattle , Cell Line , Cytotoxins/pharmacokinetics , Cytotoxins/toxicity , Diarrhea Viruses, Bovine Viral/genetics , Lactoferrin/toxicity , Muramidase/toxicity , Nisin/toxicity , RNA, Viral/biosynthesis , RNA, Viral/drug effectsABSTRACT
In this work, several normal, oil-in-water (o/w) microemulsions (MEs) were prepared using peppermint essential oil, jojoba oil, trans-anethole, and vitamin E as oil phases to test their capacity to load paclitaxel (PTX). Initially, pseudo-ternary partial phase diagrams were constructed in order to find the normal microemulsion region using d-α-tocopherol polyethylene glycol 1000 succinate (TPGS-1000) as surfactant and isobutanol (iso-BuOH) as co-surfactant. Selected ME formulations were loaded with PTX reaching concentrations of 0.6 mg mL-1 for the peppermint oil and trans-anethole MEs, while for the vitamin E and jojoba oil MEs, the maximum concentration was 0.3 mg mL-1. The PTX-loaded MEs were stable according to the results of heating-cooling cycles and mechanical force (centrifugation) test. Particularly, drug release profile for the PTX-loaded peppermint oil ME (MEPP) showed that â¼ 90% of drug was released in the first 48 h. Also, MEPP formulation showed 70% and 90% viability reduction on human cervical cancer (HeLa) cells after 24 and 48 h of exposure, respectively. In addition, HeLa cell apoptosis was confirmed by measuring caspase activity and DNA fragmentation. Results showed that the MEPP sample presented a major pro-apoptotic capability by comparing with the unloaded PTX ME sample.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Apoptosis/drug effects , Cytotoxins/chemical synthesis , Nanospheres/chemistry , Paclitaxel/chemical synthesis , Plant Oils/chemical synthesis , Antineoplastic Agents, Phytogenic/pharmacokinetics , Apoptosis/physiology , Cell Survival/drug effects , Cell Survival/physiology , Cytotoxins/pharmacokinetics , Dose-Response Relationship, Drug , Drug Liberation , HeLa Cells , Humans , Mentha piperita , Paclitaxel/pharmacokinetics , Plant Oils/pharmacokinetics , Polyethylene Glycols/chemical synthesis , Polyethylene Glycols/pharmacokinetics , Surface-Active Agents/chemical synthesis , Surface-Active Agents/pharmacokinetics , Vitamin E/chemical synthesis , Vitamin E/pharmacokineticsABSTRACT
A water soluble trinuclear copper(II) complex and a binuclear cobalt(II) complex, namely Cu3(ppbm)2(SO4)3 (1) and Co2(ppbm)2(NO3)4 (2) (ppbmâ¯=â¯2-(pyridin-2-yl)-1-(pyridin-3-ylmethyl)- 1H-benzo[d]imidazole), have been successfully synthesized and characterized by elemental analysis, IR Spectroscopy, electrospray ionization mass spectra (ESI-MS). The interaction of the new complexes with DNA has been explored using spectroscopy methods, indicating that the complexes 1 and 2 bind to DNA via noncovalent interactions. DNA cleavage experiment suggested that the complex 1 exhibits efficient DNA cleavage activities in the presence of ascorbate (Asc), hydrogen peroxide may serve as the major cleavage active species. The cytotoxicity assay showed that complex 1 exhibited significant inhibitory activity toward the proliferation of several tumor cell lines, with a lower IC50 value than cisplatin and complex 2, indicating that it had the potential to act as effective anticancer agent. The morphological staining assays showed that 1 apparently induced the TFK-1 cells apoptosis. Besides, cellular uptake experiment on TFK-1 cells revealed that complex 1 accumulates primarily inside the nucleus. The apoptosis was attributable to the metal-assisted generation of reactive oxygen species (ROS).
Subject(s)
Antineoplastic Agents , Coordination Complexes , Cytotoxins , DNA, Neoplasm/metabolism , Neoplasms , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Coordination Complexes/pharmacokinetics , Coordination Complexes/pharmacology , Cytotoxins/chemical synthesis , Cytotoxins/chemistry , Cytotoxins/pharmacokinetics , Cytotoxins/pharmacology , Humans , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathologyABSTRACT
Gemcitabine (GEM) is the first-line treatment for pancreatic adenocarcinoma (PAC) yet chemoresistance is common. Nitric oxide (NO) is the predominant species responsible for the cytotoxic action of macrophages against cancer cells yet localized delivery is difficult given the short half-life. We sought to study the effect of locally delivered NO on GEM mediated PAC cytotoxicity and the potential role of SMAD4 in this effect. We hypothesized that NO would enhance the cytotoxicity of GEM in a SMAD4 dependent manner. NO-Silica nanoparticles (NO-Si) were synthesized via a co-condensation of tetraethoxysilane with aminoalkoxysilane under high-pressure nitrous oxide. NO release was measured using chemiluminescence. A SMAD4 negative PAC cell line (SMAD4-) was made using retroviral knockdown of Panc1 PAC cells. Panc1 and SMAD4- cells were treated with gemcitabine (100 nm (hi) to 30 µm (lo)), 30 mg NOSi particles, or both (NOSihi or NOSilo) and cell viability assessed. NoSi reduced cell viability by 25.99% in Panc1 and 24.38% in SMAD4-. When combined with gemcitabine, further reductions were seen in a dose dependent manner for both cell lines. We have demonstrated the in-vitro dose dependent cytotoxic effects of NOSi. When combined with GEM there is a synergistic effect resulting in improved cytotoxicity seen in both Panc1 and SMAD4- PAC cells with a differential pattern of cell death seen at high concentrations of NO. These findings suggest not only that NO is useful chemosensitizing agent but that SMAD4- may play a role in its synergism with GEM.