RESUMO
A molecularly imprinting polymer (MIP) carrier with pH-responsivity was designed to construct a drug delivery system (DDS) focusing on controlled and sustainable capecitabine (CAPE) release. The pH-responsive characteristic was achieved by the functionalization of SiO2 substrate with 4-formylphenylboronic acid, accompanied by the introduction of fluorescein isothiocyanate for the visualization of the intracellular localization of the nanocarrier. Experimental results indicated that CAPE was adsorbed onto the drug carrier with satisfactory encapsulation efficiency. The controlled release of CAPE was realized based on the break of borate ester bonds between -B(OH)2 and cis-diols in the weakly acidic environment. Density functional theory computations were conducted to investigate the adsorption/release mechanism. Moreover, in vitro experiments confirmed the good biocompatibility and ideal inhibition efficiency of the developed DDS. The MIP can act as an eligible carrier and exhibits the great potential in practical applications for tumor treatment.
Assuntos
Capecitabina , Portadores de Fármacos , Polímeros Molecularmente Impressos , Capecitabina/química , Concentração de Íons de Hidrogênio , Portadores de Fármacos/química , Polímeros Molecularmente Impressos/química , Humanos , Liberação Controlada de Fármacos , Antimetabólitos Antineoplásicos/química , Preparações de Ação Retardada/química , Sobrevivência Celular/efeitos dos fármacos , Teoria da Densidade Funcional , Polímeros/química , Polímeros/síntese químicaRESUMO
The degradation of three anti-cancer drugs (ADs), Capecitabine (CAP), Bicalutamide (BIC) and Irinotecan (IRI), in ultrapure water by ozonation and UV-irradiation was tested in a bench-scale reactor and AD concentrations were measured through ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). A low-pressure mercury UV (LP-UV) lamp was used and degradation by UV (λ = 254 nm) followed pseudo-first order kinetics. Incident radiation in the reactor was measured via chemical actinometry using uridine. The quantum yields (φ) for the degradation of CAP, BIC and IRI were 0.012, 0.0020 and 0.0045 mol Einstein-1, respectively. Ozone experiments with CAP and IRI were conducted by adding ozone stock solution to the reactor either with or without addition of tert-butanol (t-BuOH) as radical quencher. Using this experimental arrangement, no degradation of BIC was observed, so a semi-batch setup was employed for the ozone degradation experiments of BIC. Without t-BuOH, apparent second order reaction rate constants for the reaction of the ADs with molecular ozone were determined to be 3.5 ± 0.8 â 103 L mol-1 s-1 (CAP), 7.9 ± 2.1 â 10-1 L mol-1 s-1 (BIC) and 1.0 ± 0.3 â 103 L mol-1 s-1 (IRI). When OH-radicals (âOH) were quenched, rate constants were virtually the same for CAP and IRI. For BIC, a significantly lower constant of 1.0 ± 0.5 â 10-1 L mol-1 s-1 was determined. Of the tested substances, BIC was the most recalcitrant, with the slowest degradation during both ozonation and UV-irradiation. The extent of mineralization was also determined for both processes. UV irradiation was able to fully degrade up to 80% of DOC, ozonation up to 30%. Toxicity tests with Daphnia magna (D. magna) did not find toxicity for fully degraded solutions of the three ADs at environmentally relevant concentrations.
Assuntos
Anilidas , Antineoplásicos , Capecitabina , Irinotecano , Nitrilas , Ozônio , Compostos de Tosil , Raios Ultravioleta , Poluentes Químicos da Água , Ozônio/química , Nitrilas/química , Poluentes Químicos da Água/química , Irinotecano/química , Anilidas/química , Capecitabina/química , Compostos de Tosil/química , Antineoplásicos/química , Cinética , Espectrometria de Massas em Tandem , Cromatografia Líquida de Alta PressãoRESUMO
To improve the antitumor effect of combined capecitabine (CAP) and osimertinib (OSI) therapy and quickly and efficiently reduce tumor volumes for preoperative chemotherapy, we designed a compound CAP colon-targeted microparticle (COPMP) prepared by coaxial electrospray. COPMP is a core-shell microparticle composed of a Eudragit S100 outer layer and a CAP/OSI-loaded PLGA core. In this study, we characterized its size distribution, drug loading (DL), encapsulation efficiency (EE), differential scanning calorimetry (DSC), Fourier transform infrared spectra (FTIR), in vitro release, formula ratio, cellular growth inhibition, and in vivo antitumor efficacy. COPMP is of spherical appearance with a size of 1.87 ± 0.23 µm. The DLs of CAP and OSI are 4.93% and 4.95%, respectively. The DSC showed that the phase state of CAP and OSI changed after encapsulation. The FTIR results indicated good compatibility between the drug and excipients. The release curve showed that CAP and OSI were released in a certain ratio. They were barely released prior to 2 h (pH 1.0), less than 50% was released between 3 and 5 h (pH 6.8), and sustained release of up to 80% occurred between 6 and 48 h (pH 7.4). CAP and OSI demonstrated a synergistic effect on HCT-116 cells. In a colon tumor model, the tumor inhibition rate after oral administration of COPMP reached 94% within one week. All the data suggested that COPMP promotes the sustained release of CAP and OSI in the colon, which provides a preoperative chemotherapy scheme for the treatment of colon cancer.
Assuntos
Colo , Neoplasias do Colo , Capecitabina/química , Capecitabina/farmacologia , Colo/metabolismo , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/metabolismo , Preparações de Ação Retardada/química , Liberação Controlada de Fármacos , Humanos , Tamanho da PartículaRESUMO
Cancer is the leading cause of death worldwide. Capecitabine (CP) shows severe side effects because of early metabolism in stomach that affects the normal cells and organs, particularly liver and stomach. In this scope, we report the biocompatible, nontoxic polymeric thin films loaded with anti-cancer drug, CP for target specific, sublingual delivery of CP. Chitosan (CS) and polyvinyl alcohol (PVA) were used as biodegradable polymers alongwith glutaraldehyde (GLA) cross linker. CP-loaded thin films (TFCP1-TFCP5) were fabricated by solvent casting method. The results of Fourier transform infrared spectroscopy confirmed the presence of CP and polymers (CS and PVA) with GLA which binds through hydrogen bonding, and compatibility of drug with different excipients. Thermogravemetric analysis showed that the thin films are highly stable while differential scanning calorimeter thermograms confirmed the complete miscibility/entrapment of CP within PVA/CS thin film matrix. X-ray diffraction patterns revealed the molecular ineractions between CP and polymer matrix. High degree of swelling index of thin films at pH 7.4 was observed in comparison to pH 5.5. CP release studies in acetate (pH 5.5) and phosphate buffer (pH 7.4) showed that the thin films swell and result in drug diffusion faster in phosphate buffer through diffusion governed by Higuchi's model. Cytotoxicity results displayed that CPTFs killed MCF-7 and T47D (human breast adenocarcinoma) cells more effectively as compared to CP alone. The results of adhesion assay also showed that the PVA and CS both are safe and biocompatible. TFCP1 and TFCP3 thin films efficiently induced the apoptosis as compared to CP alone. The improved ability of TFCP1 and TFCP3 to induce cytotoxicity in MCF-7 cells reflects the potential of these thin films for targeted drug delivery. The CPTFs were stable for 4 months at 4 °C/60% ± 2%RH and 25 °C/70% ± 2%RH. In conclusion, the thin film formulations showed target specific controlled and burst release properties and thus could prove to be effective for human breast cancer treatment.
Assuntos
Antimetabólitos Antineoplásicos , Materiais Biocompatíveis/química , Capecitabina , Sistemas de Liberação de Medicamentos/métodos , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/farmacologia , Capecitabina/química , Capecitabina/farmacocinética , Capecitabina/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Células MCF-7 , Teste de Materiais , Álcool de Polivinil/químicaRESUMO
An ultrasonic-assisted dispersive solid-phase microextraction was developed by a multi-stimuli responsive molecularly imprinted polymer based on chain transfer agent-modified chitosan nanoparticles for enrichment and separation of trace capecitabine in a real sample. The synthesized particles were carefully characterized and it was found that a uniform pH-sensitive imprinted polymeric shell is obtained on the surface of Fe3O4@chitosan core with enough saturation magnetization (29 emu g-1). Desirable adsorption capacity (91 mg g-1) and high imprinting factor (IF = 3.6) toward capecitabine were exhibited by the Langmuir isotherm model. Under optimized conditions, which were achieved by experimental design, the detection limit (S/N = 3) was 1.9 ng mL-1. The obtained relative mean recoveries of capecitabine using high-performance liquid chromatography were in the range of 93 to 102% in a human plasma sample with RSD less than 5.5%. Graphical abstract Schematic representation of ultrasonic-assisted dispersive solid-phase microextraction by multi-stimuli responsive molecularly imprinted polymer based on chain transfer agent-modified chitosan nanoparticles and high-performance liquid chromatography for enrichment and separation of capecitabine in the real sample.
Assuntos
Antineoplásicos/sangue , Capecitabina/sangue , Quitosana/química , Nanopartículas de Magnetita/química , Polímeros Molecularmente Impressos/química , Adsorção , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Capecitabina/química , Capecitabina/isolamento & purificação , Cromatografia Líquida de Alta Pressão , Humanos , Limite de Detecção , Microextração em Fase Sólida/métodos , Ondas UltrassônicasRESUMO
BACKGROUND: Nanocarriers improve the efficacy of drugs by facilitating their specific delivery and protecting them from external environment resulting in a better performance against diseases. OBJECTIVE: In this study, it was aimed to improve the efficacy of capecitabine against colorectal cancer by its entrapment in niosomes. Ether injection method was used to prepare niosomes composed of span 20 and cholesterol. METHODS: Niosomes were evaluated by evaluating the entrapment efficiency, in-vitro drug release and cytotoxicity of capecitabine loaded niosomes. Niosomes were characterized by particle size analysis, transmission electron microscopy, Fourier transform infrared spectroscopy and differential scanning calorimetry for surface morphology and drug excipient interactions. RESULTS: High encapsulation efficiency (90.55%) was observed, which is anticipated to resolve the multi-drug resistance problem. Reported particle size was 180.9 + 5 nm with a negative zeta potential - 21 + 0.5 mV and the kinetic study showed a concentration-dependent release of the drug from the niosome. DSC study proved entrapment of the entire drug and its non-covalent bonding with the excipients. Cytotoxicity study of niosomes on CaCO2 cell line showed an improved IC50 value as compared to the free drug. CONCLUSION: Enhanced cytotoxicity observed in the results further supports the suitability of niosome as a nanocarrier for pharmaceutical drug delivery.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Capecitabina/administração & dosagem , Animais , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacocinética , Disponibilidade Biológica , Células CACO-2 , Capecitabina/química , Capecitabina/farmacocinética , Proliferação de Células/efeitos dos fármacos , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Lipossomos , Ratos WistarRESUMO
The present research reports the beneficial effects of surface modified chitosan and tumor-homing peptide conjugated liposomes of capecitabine (CAP) for treating breast cancer. Liposomal formulation of CAP was prepared by film hydration method using cholesterol-THP conjugate (CTHP-CAP-LPs) to achieve active targeting through HER2 receptors. CTHP-CAP-LPs significantly improved the specificity and efficacy of CAP by improving cell uptake, cytotoxicity and tumor regression in tumor bearing mice. CTHP-CAP-LPs, therefore, is a promising approach to improve the anticancer effects of CAP.
Assuntos
Antimetabólitos Antineoplásicos , Neoplasias da Mama , Quitosana , Peptídeos , Receptor ErbB-2 , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Capecitabina/química , Capecitabina/farmacologia , Linhagem Celular Tumoral , Quitosana/química , Quitosana/farmacologia , Feminino , Humanos , Lipossomos , Peptídeos/química , Peptídeos/farmacologia , Receptor ErbB-2/agonistas , Receptor ErbB-2/metabolismoRESUMO
Objective: The main aim of this research work was to develop and evaluate cost effective modified release tablets of Capecitabine (CAP) without utilizing coating techniques.Methods: The tablets were prepared by non-aqueous wet granulation method. Hydroxypropyl cellulose (HPC) was used as an extended release matrix former and sodium alginate (SA) was used as sustained release agent due to its gel forming ability. 32 full factorial design was used to study the effect of the independent variables i.e. HPC and SA on dependent variables, in vitro drug release and swelling index. The physiochemical properties of the drug were analyzed by ultraviolet (UV), fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and powder X-ray diffraction (P-XRD). The formulated tablets were evaluated for hardness, thickness, weight variation, content uniformity, swelling index, and in vitro drug release study.Results: The FTIR and DSC studies confirmed that there was no any interaction between drug, polymers and excipients. Also from DSC and P-XRD studies it was clear that the crystalline nature of CAP was remain unchanged in the optimized formulation tablet. Formulation F8 retarded the drug release up to 24 h with the optimum concentration of the both the polymers.Conclusion: We have successfully developed the modified release tablets of CAP with the combination of diffusion and erosion controlled type of drug release mechanism.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Capecitabina/administração & dosagem , Excipientes/química , Polímeros/química , Alginatos/química , Antimetabólitos Antineoplásicos/química , Capecitabina/química , Celulose/análogos & derivados , Celulose/química , Química Farmacêutica , Cristalização , Preparações de Ação Retardada , Liberação Controlada de Fármacos , ComprimidosRESUMO
The bioanalysis of the oral anticancer drug capecitabine and its metabolites has been investigated extensively over the past years. This paper reviews methods for the bioanalysis of capecitabine and its metabolites. The focus of this review will be on sample pre-treatment, chromatography and detection. Furthermore, the choice of standards and analytical problems encountered during analysis of capecitabine and its metabolites in biological matrices will be discussed. The major challenges in the bioanalysis of capecitabine and its metabolites are the simultaneous extraction and analysis due to the differences in polarity of the analytes. Furthermore we evaluate currently described methods for the quantification of capecitabine and its metabolites. Future wishes and perspectives are stated that could serve as an inspiration for further development of assays for the quantification of capecitabine and its metabolites.
Assuntos
Capecitabina , Cromatografia Líquida , Animais , Capecitabina/análise , Capecitabina/química , Capecitabina/isolamento & purificação , Fracionamento Químico , Humanos , Espectrometria de Massas , CamundongosRESUMO
In this work, nanocomposite hydrogel drug delivery systems based on polyvinyl alcohol and montmorillonite loaded with the capecitabine, as an anti-cancer drug, were developed for oral administration. The gel fraction and swelling ability of the prepared nanocomposite hydrogels were experimentally measured. In vitro release kinetics of capecitabine in nanocomposite hydrogel drug delivery systems were studied. In vitro flow cytometry assay was utilized to exhibit the anti-cancer activity of the prepared nanocomposite hydrogel drug delivery systems against 4T1 cancer cell line. The anti-tumor efficacy of the nanocomposite hydrogel drug delivery systems was also studied in vivo on animal models. The results showed that the amount of montmorillonite incorporated into the nanocomposite hydrogel drug delivery systems could be recognized as a key parameter to adjust the values of the gel fraction, swelling and capecitabine release rate in a manner which by increasing the montmorillonite content, the gel fraction is increased while the swelling and drug release rate are decreased. The flow cytometry results demonstrated the better anti-cancer activity of the capecitabine-loaded nanocomposite hydrogel drug delivery systems as compared with the pure capecitabine. The in vivo assays indicated that the administration of nanocomposite hydrogel drug delivery systems had a significant effect on the reduction of the tumor growth in animal models as compared with pure capecitabine administration. In general, the prepared nanocomposite hydrogel drug delivery systems exhibited a suitable efficacy against 4T1 cancer cell line both in vitro and in vivo and they could be considered as promising candidates for controlled release of anti-cancer drugs in chemotherapy with enhanced therapeutic effects.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/patologia , Capecitabina/química , Capecitabina/farmacologia , Portadores de Fármacos/química , Nanogéis/química , Animais , Bentonita/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Liberação Controlada de Fármacos , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Nanocompostos/química , Álcool de Polivinil/química , Carga Tumoral/efeitos dos fármacosRESUMO
Theranostic nanoplatforms haev been proven to be a feasible strategy against cancer for convenient diagnosis, efficient drug release, and reduced side effects. However, the drug leakage during blood circulation, poor cellular uptake of drug-loaded nanoparticles, and insufficient drug release still remain to be overcome. Herein, a hierarchical pH and reactive oxygen species (ROS)-responsive nanoplatform is constructed labeling with a two-photon fluorophore developed by us, aiming for a programmed drug delivery and an intensive two-photon bioimaging. With the capecitabine (Cap) conjugated, the prodrug polymer PMPC-b-P[MPA(Cap)-co-TPMA]-PAEMA (PMMTAb-Cap) can be self-assembled into the core-shell structured micelles, which can stay stable in the blood stream. Once the micelles accumulate at the tumor tissue, the outside PMPC shell can be desquamated while the inner PAEMA become hydrophilic and electropositive under the acidic extracellular tumor microenvironment, leading to a shrunken micellar size for the better penetration along with enhanced endocytosis. After cellular internalization, the overexpressed intracellular ROS can eventually trigger the drug delivery for an accurate tumor therapy, which is confirmed by the in vivo antitumor experiments. Furthermore, the in vivo micellar biodistribution can be traced by a deep tissue imaging up to 150 µm because of the aggregation-induced emission active two-photon fluorophore. As a theranostic nanoplatform with two-photon bioimaging and hierarchical responsiveness, these PMMTAb-Cap micelles can be a potential candidate for tumor theranostical applications.
Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Animais , Capecitabina/química , Capecitabina/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Imagem Molecular/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Fótons , Polímeros/química , Polímeros/farmacologia , Espécies Reativas de Oxigênio/química , Nanomedicina Teranóstica , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Capecitabine is an oral prodrug of the anticancer drug 5-fluorouracil (5-FU). The primary aim of this study was to develop a pharmacokinetic model for capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine (dFCR), 5'-deoxy-5-fluorouridine (dFUR), 5-FU, and fluoro-ß-alanine (FBAL) using data from a heterogeneous population of cancer patients (n = 237) who participated in seven clinical studies. A four-transit model adequately described capecitabine absorption. Capecitabine, dFCR, and FBAL pharmacokinetics were well described by two-compartment models, and dFUR and 5-FU were subject to flip-flop pharmacokinetics. Partial and total gastrectomy were associated with a significantly faster capecitabine absorption resulting in higher capecitabine and metabolite peak concentrations. Patients who were heterozygous polymorphic for a genetic mutation encoding dihydropyrimidine dehydrogenase, the DPYD*2A mutation, demonstrated a 21.5% (relative standard error 11.2%) reduction in 5-FU elimination. This comprehensive population model gives an extensive overview of capecitabine and metabolite pharmacokinetics in a large and heterogeneous population of cancer patients.
Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Capecitabina/farmacocinética , Di-Hidrouracila Desidrogenase (NADP)/genética , Neoplasias/tratamento farmacológico , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Capecitabina/administração & dosagem , Capecitabina/química , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacocinética , Feminino , Floxuridina/farmacocinética , Gastrectomia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/genética , Variantes Farmacogenômicos , Pró-FármacosRESUMO
A combination of biopolymers sodium alginate and locust bean gum has been used to prepare an interpenetrating polymeric network of an anticancer drug Capecitabine by ionotropic gelation method. For the optimization 32 levels, a full factorial design was employed to examine the influence of independent factors, i.e. polymer ratio and cross-linker concentration on responses particle size and drug entrapment. The obtained optimized formulation was examined for solid-state characterization, swelling study, in vitro drug release, SRB study, oral toxicity study, in vivo pharmacokinetic and in vivo antitumor study. The results of all the studies performed were found suitable in extending the release of a short elimination half-life drug with improved bioavailability and suggesting it to be safe and effective for oral drug delivery in treating colon cancer.
Assuntos
Alginatos/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Capecitabina/química , Capecitabina/farmacologia , Galactanos/química , Mananas/química , Gomas Vegetais/química , Polímeros/química , Animais , Biopolímeros/química , Neoplasias do Colo/tratamento farmacológico , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microesferas , Tamanho da Partícula , Ratos , Ratos WistarRESUMO
This study aimed to evaluate antiproliferative and proapoptotic effects of Capecitabine bonded silver particles on human breast cancer cells (MCF-7). Different sizes of Ag NPs (in sizes 5, 10, 15, 30â¯nm) were synthesized. The characterization of silver and drug-bonded silver nanoparticles was performed through UV-VIS, FTIR, and SEM analysis. Silver and drug-bonded silver nanoparticles were measured by zetasizer. Antiproliferative and proapoptotic effects of capecitabine, silver and drug-bonded silver nanoparticles were evaluated using XTT, Anneksin V, respectively. According to the results, silver nanoparticles of 10â¯nm size have shown the lowest toxic effect. Drug-bonded nanoparticles significantly increased the number of early and late apoptotic cells on MCF-7 cells.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Capecitabina/farmacologia , Nanopartículas Metálicas , Prata/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Capecitabina/química , Proliferação de Células/efeitos dos fármacos , Humanos , Células MCF-7 , Nanopartículas Metálicas/química , Prata/químicaRESUMO
Capecitabine as a prodrug of 5-Fluorouracil plays an important role in the treatment of breast and gastrointestinal cancers. Herein, in view of the importance of this drug in chemotherapy, interaction mechanism between Capecitabine (CAP) and human serum albumin (HSA) as a major transport protein in the blood circulatory system has been investigated by using a combination of spectroscopic and molecular modeling methods. The fluorescence spectroscopic results revealed that capecitabine could effectively quench the intrinsic fluorescence of HSA through a static quenching mechanism. Evaluation of the thermodynamic parameters suggested that the binding process was spontaneous while hydrogen bonds and van der Waals forces played a major role in this interaction. The value of the binding constant (Kbâ¯=â¯1.820â¯×â¯104) suggested a moderate binding affinity between CAP and HSA which implies its easy diffusion from the circulatory system to the target tissue. The efficiency of energy transfer and the binding distance between the donor (HSA) and acceptor (CAP) were determined according to forster theory of nonradiation energy transfer as 0.410 and 4.135â¯nm, respectively. Furthermore, UV-Vis spectroscopic results confirmed that the interaction was occurred between HSA and CAP and caused conformational and micro-environmental changes of HSA during the interaction. Multivariate curve resolution-alternating least square (MCR-ALS) methodology as an efficient chemometric tool was used to separate the overlapped spectra of the species. The MCR-ALS result was exploited to estimate the stoichiometry of interaction and to provide concentration and structural information about HSA-CAP interactions. Molecular docking studies suggested that CAP binds mainly to the subdomain IIA of HSA, which were compatible with those obtained by experimental data. Finally, molecular dynamics simulation (MD) was performed on the best docked complex by considering the permanence and flexibility of HSA-CAP complex in the binding site. MD result showed that CAP could steadily bind to HSA in the site I based on the formation of hydrogen bond and π-π stacking interaction in addition to hydrophobic force.
Assuntos
Capecitabina/metabolismo , Pró-Fármacos/metabolismo , Albumina Sérica Humana/metabolismo , Sítios de Ligação , Capecitabina/química , Humanos , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Pró-Fármacos/química , Ligação Proteica , Albumina Sérica Humana/química , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , TermodinâmicaRESUMO
Capecitabine (CAP) is an FDA-approved and frequently used chemotherapeutic agent for the treatment of various cancers. However, there are some side effects and chemoresistance limiting its use. Nanotechnological approaches can enhance the efficacy of anticancer drugs. In this study, CAP-loaded nanoniosomes were prepared. Nanoniosomes were prepared by the method of thin film hydration wherein CAP was loaded into the nanoniosomes. Nanoniosomes were then characterized by field emission scanning electron microscopy and (particle) vesicle size analysis. The cytotoxicity effect of the nanoniosomes were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. CAP was loaded into the nanoniosomes and loading capacity and entrapment efficiency were determined. The vesicle size of the nanoniosomes was obtained in the nanometer scale, and CAP release profiles from the nanoniosomes were also obtained. Finally, the cytotoxicity effect of CAP and CAP-loaded nanoniosomes were evaluated toward MCF7 and PANC1 cell lines. The nanoniosomes with an amphipathic structure can penetrate into the cells with an enhanced release rate. These caused the toxicity of drug in the nanoniosomes to be higher than the free drug.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Capecitabina/química , Capecitabina/farmacologia , Nanoestruturas/química , Calibragem , Sobrevivência Celular/efeitos dos fármacos , Humanos , Lipossomos , Células MCF-7RESUMO
Molecularly imprinted polymers (MIPs) have drawn extensive attention as carriers on drug delivery. However, most of MIPs suffer from insufficient drug loading capacity, burst release of drugs and/or low bioavailability. To solve the issues, this study designed an imprinted material with superior floating nature for oral drug delivery system of capecitabine (CAP) rationally. The MIPs was synthesized in the presence of 4-methylphenyl dicyclohexyl ethylene (liquid crystalline, LC) and polyhedral oligomeric silsesquioxanes (POSS) via polymerization reaction. The LC-POSS MIPs had extended release of the template molecules over 13.4â¯h with entrapment efficiency of 20.53%, diffusion coefficient of 2.83â¯×â¯10-11â¯cm2â¯s-1, and diffusion exponent of 0.84. Pharmacokinetic studies further revealed the prolong release and high relative bioavailability of CAP in vivo of rats, showing the effective floating effect of the LC-POSS MIPs. The in vivo images revealed visually that the gastroretentive time of the LC-POSS MIPs was longer than non-LC-POSS imprinted polymers. The physical characteristics of the polymers were also characterized by nitrogen adsorption experiment, scanning electron microscopy, thermogravimetric analysis and differential scanning calorimetry analysis. As a conclusion, the LC-POSS MIPs can be used as an eligible CAP carrier and might hold great potential in clinical applications for sustained release drug.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Capecitabina/administração & dosagem , Impressão Molecular , Compostos de Organossilício/administração & dosagem , Polímeros/administração & dosagem , Animais , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacocinética , Capecitabina/química , Capecitabina/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos , Humanos , Cristais Líquidos/química , Células MCF-7 , Masculino , Modelos Moleculares , Compostos de Organossilício/química , Compostos de Organossilício/farmacocinética , Polímeros/química , Polímeros/farmacocinética , Ratos WistarRESUMO
The current research is focused to develop and investigate the toxicity and penetration potential of biocompatible chitosan nanogel encapsulating capecitabine by ionic interaction mechanism exhibiting pH triggered transdermal targeting. The nanogel (CPNL) was synthesized by ion gelation mechanism using Pluronic F 127 and surface decoration by Transcutol as non-ionic penetration enhancer. The CPNL possesses fine morphology and nano size range when evaluated by TEM, SEM and DLS analysis with cationic charge and slightly acidic pH assayed by zeta potential and pH analysis. It showed pH responsive drug release characteristics mimicking the skin cancer micro-environment. The MTT assay and apoptotic index of CPNL on HaCaT cell line elaborated optimal cell toxicity and retention on 24h of exposure. The ex-vivo skin penetration analysis exhibited noteworthy diffusion and penetration caliber through concentration depth profile, steady state flux and fluorescent skin imaging on porcine tissue. Overall outcomes suggested CPNL as a potent alternative biocompatible, transdermal nanotherapy against skin cancer displaying significant penetration caliber with enhance toxicity on cancerous cell.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Nanoestruturas/química , Neoplasias Cutâneas/tratamento farmacológico , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Capecitabina/química , Capecitabina/farmacologia , Capecitabina/uso terapêutico , Linhagem Celular , Quitosana/química , Difusão , Liberação Controlada de Fármacos , Etilenoglicóis/química , Géis , Humanos , Concentração de Íons de Hidrogênio , Tamanho da Partícula , Permeabilidade , Poloxâmero/química , Pele/metabolismo , Propriedades de SuperfícieRESUMO
The interaction mechanism and binding mode of capecitabine with ctDNA was extensively investigated using docking and molecular dynamics simulations, fluorescence and circular dichroism (CD) spectroscopy, DNA thermal denaturation studies, and viscosity measurements. The possible binding mode and acting forces on the combination between capecitabine and DNA had been predicted through molecular simulation. Results indicated that capecitabine could relatively locate stably in the G-C base-pairs-rich DNA minor groove by hydrogen bond and several weaker nonbonding forces. Fluorescence spectroscopy and fluorescence lifetime measurements confirmed that the quenching was static caused by ground state complex formation. This phenomenon indicated the formation of a complex between capecitabine and ctDNA. Fluorescence data showed that the binding constants of the complex were approximately 2 × 104 M-1. Calculated thermodynamic parameters suggested that hydrogen bond was the main force during binding, which were consistent with theoretical results. Moreover, CD spectroscopy, DNA melting studies, and viscosity measurements corroborated a groove binding mode of capecitabine with ctDNA. This binding had no effect on B-DNA conformation.
Assuntos
Antimetabólitos Antineoplásicos/química , Capecitabina/química , DNA/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Algoritmos , Animais , Antimetabólitos Antineoplásicos/farmacologia , Sítios de Ligação , Capecitabina/farmacologia , Bovinos , Modelos Teóricos , Estrutura Molecular , Conformação de Ácido Nucleico , Reprodutibilidade dos Testes , Reologia , Análise EspectralRESUMO
The present study aims to investigate the efficacy of the novel biopolymeric complex multiparticulate system consisting of chitosan succinate and alginate for the capecitabine-targeted delivery to colon cancer. A Box-Behnken design was used to optimize the CS-SA beads by considering the effect of three factors: CS (A;X1), CaCl2 (B;X2), and SA (C;X3), on the response variables Y1 (EE), Y2 (Size), and Y3 (Release). The results of response surface plots allowed an optimized bead to be identified with high drug EE and maximum drug release at colon. The swelling index showed that the beads reached a maximum good swelling at pHâ¯7.4, and nil or little swelling at acidic pH, which proves that the beads completely protect the release of drug. The in vitro release portrayed a maximum release at pHâ¯7.4, due to the large swelling force that was created by electrostatic repulsion between the ionized carboxylic acid groups of the CS-SA network. In vitro cytotoxicity assay (MTT) of CS-SA beads shows inhibition of the proliferation of HT-29 tumour cell to induce apoptosis over a longer period of time. The above results show that CS-SA beads prolong the release of CP in the colonic region, and also enhance antitumor efficacy.