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1.
AAPS PharmSciTech ; 22(5): 203, 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34244867

RESUMO

Capsanthin, a brightly orange-red-coloured pigment responsible for the peculiar red colour of paprika fruits (Capsicum annuum), belongs to xanthophylls, a class of oxygen-containing carotenoids. The characteristic chemical structure of capsanthin containing a keto group in conjunction with a long chain of 11 conjugated dienes is responsible for its strong radical scavenging and singlet oxygen quenching ability. Chemopreventive, antitumour, skin photo-protective, anti-inflammatory, and antidiabetic activities demonstrated by capsanthin are a consequence of its potent antioxidant action. Anti-obesity, anti-adipogenic, and antihyperlipidaemic activities are some of the more important features of capsanthin. With natural origin, bright red colour, and array of health benefits, capsanthin has a potential to be translated into a commercial cosmeceutical, nutraceutical, and/or pharmaceutical. However, the very low aqueous solubility of capsanthin is responsible for its highly variable and poor oral bioavailability. Moreover, its susceptibility to degradation due to heat, light, oxygen, and moisture poses challenges in the development of stable formulations for this otherwise meritorious compound. The current review presents various pharmacological activities of capsanthin and their underlying mechanisms. The review further discusses hitherto explored formulation strategies to improve solubility and stability of capsanthin. Graphical abstract.


Assuntos
Animais , Fármacos Antiobesidade/administração & dosagem , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Capsicum/química , Humanos , Hipolipemiantes/administração & dosagem , Hipolipemiantes/farmacologia , Hipolipemiantes/uso terapêutico , Xantofilas/administração & dosagem , Xantofilas/química , Xantofilas/farmacologia , Xantofilas/uso terapêutico
2.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206347

RESUMO

In this study, an amphiphilic conjugate based on mPEG and cholesterol-modified chitosan with hydrazone bonds in the molecules (mPEG-CS-Hz-CH) was successfully synthesized. Using the polymer as the carrier, the paclitaxel (PTX)-loaded mPEG-CS-Hz-CH micelles were prepared by an ultrasonic probe method. The mean particle size and zeta potential of the optimized PTX-loaded micelles were 146 ± 4 nm and +21.7 ± 0.7 mV, respectively. An in vitro drug release study indicated that the PTX-loaded mPEG-CS-Hz-CH micelles were stable under normal physiological conditions (pH 7.4), whereas rapid drug release was observed in the simulated tumor intracellular microenvironment (pH 5.0). An in vitro cytotoxicity study demonstrated the non-toxicity of the polymer itself, and the PTX-loaded micelles exhibited superior cytotoxicity and significant selectivity on tumor cells. An in vivo antitumor efficacy study further confirmed that the PTX-loaded micelles could improve the therapeutic efficacy of PTX and reduce the side effects. All these results suggested that the mPEG-CS-Hz-CH micelles might be promising pH-sensitive nanocarriers for PTX delivery.


Assuntos
Quitosana/química , Sistemas de Liberação de Medicamentos , Micelas , Neoplasias/tratamento farmacológico , Paclitaxel/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêutico , Linhagem Celular , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Humanos , Células MCF-7 , Paclitaxel/uso terapêutico , Tamanho da Partícula , Polímeros
3.
Int J Nanomedicine ; 16: 4001-4016, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34135585

RESUMO

Background: Tumor angiogenesis has been proven to potentiate tumor growth and metastasis; therefore, the strategies targeting tumor-related angiogenesis have great potentials in antitumor therapy. Methods: Here, the GA&Gal dual-ligand-modified liposomes co-loaded with curcumin and combretastatin A-4 phosphate (CUCA/GA&Gal-Lip) were prepared and characterized. A novel "BEL-7402+HUVEC" co-cultured cell model was established to mimic tumor microenvironment. The cytotoxicity and migration assays were performed against the novel co-cultured model. Angiogenesis ability was evaluated by tube formation test, and in vivo metastatic ability was evaluated by lung metastasis test. Results: The result demonstrated that dual-ligand-modified liposomes showed greater inhibition of tumor angiogenesis and metastasis in comparison with other combined groups. Significantly, the mechanism analysis revealed that curcumin and combretastatin A-4 phosphate could inhibit tumor angiogenesis and metastasis via down-regulation of VEGF and VEGFR2 expression, respectively, and that GA&Gal-Lip could improve antitumor effect by GA/Gal-mediated active-targeting delivery. Conclusion: CUCA/GA&Gal-Lip hold great potentials in hepatoma-targeting delivery of antitumor drugs and can achieve anti-angiogenic and anti-metastatic effects by simultaneously blocking VEGF/VEGFR2 signal pathway, therefore exhibiting superior anti-hepatoma efficacy.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Lipossomos/farmacologia , Neovascularização Patológica/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Curcumina/administração & dosagem , Curcumina/farmacocinética , Liberação Controlada de Fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Ligantes , Lipossomos/administração & dosagem , Lipossomos/química , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Camundongos Endogâmicos BALB C , Estilbenos/administração & dosagem , Estilbenos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Toxicol Appl Pharmacol ; 423: 115576, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34000264

RESUMO

Metastatic breast cancer is a prevalent life-threatening disease. Paclitaxel (PTX) is widely used in metastatic breast cancer therapy, but the side effects limit its chemotherapeutic application. Multidrug strategies have recently been used to maximize potency and decrease the toxicity of a particular drug by reducing its dosage. Therefore, we have evaluated the combined anti-cancerous effect of PTX with tested natural compounds (andrographolide (AND), silibinin (SIL), mimosine (MIM) and trans-anethole (TA)) using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, trypan blue dye exclusion assay, proliferating cell nuclear antigen (PCNA) staining, network pharmacology, molecular docking, molecular dynamics (MD) and in vivo chick chorioallantoic membrane (CAM) angiogenesis assay. We observed a reduction in the IC50 value of PTX with tested natural compounds. Further, the network pharmacology-based analysis of compound-disease-target (C-D-T) network showed that PTX, AND, SIL, MIM and TA targeted 55, 61, 56, 31 and 18 proteins of metastatic breast cancer, respectively. Molecular docking results indicated that AND and SIL inhibited the C-D-T network's core target kinase insert domain receptor (KDR) protein more effectively than others. While MD showed that the binding of AND with KDR was stronger and more stable than others. In trypan blue dye exclusion assay and PCNA staining, AND and SIL along with PTX were found to be more effective than PTX alone. CAM assay results suggested that AND, SIL and TA increase the anti-angiogenic potential of PTX. Thus, natural compounds can be used to improve the anti-cancer potential of PTX.


Assuntos
Antineoplásicos Fitogênicos/metabolismo , Produtos Biológicos/metabolismo , Neoplasias da Mama/metabolismo , Paclitaxel/metabolismo , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Produtos Biológicos/administração & dosagem , Produtos Biológicos/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Embrião de Galinha , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Simulação de Acoplamento Molecular/métodos , Paclitaxel/administração & dosagem , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Resultado do Tratamento
5.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808235

RESUMO

Biocompatible nanoparticles (NPs) containing polymers, lipids (liposomes and micelles), dendrimers, ferritin, carbon nanotubes, quantum dots, ceramic, magnetic materials, and gold/silver have contributed to imaging diagnosis and targeted cancer therapy. However, only some NP drugs, including Doxil® (liposome-encapsulated doxorubicin), Abraxane® (albumin-bound paclitaxel), and Oncaspar® (PEG-Asparaginase), have emerged on the pharmaceutical market to date. By contrast, several phytochemicals that were found to be effective in cultured cancer cells and animal studies have not shown significant efficacy in humans due to poor bioavailability and absorption, rapid clearance, resistance, and toxicity. Research to overcome these drawbacks by using phytochemical NPs remains in the early stages of clinical translation. Thus, in the current review, we discuss the progress in nanotechnology, research milestones, the molecular mechanisms of phytochemicals encapsulated in NPs, and clinical implications. Several challenges that must be overcome and future research perspectives are also described.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Nanopartículas/química , Nanotecnologia/métodos , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Humanos , Sistema Fagocitário Mononuclear/efeitos dos fármacos , Nanopartículas/administração & dosagem , Nanopartículas/uso terapêutico , Nanotubos de Carbono , Compostos Fitoquímicos/administração & dosagem , Pontos Quânticos
6.
Toxicol Appl Pharmacol ; 419: 115511, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33819459

RESUMO

Hesperetin (HSP) has excellent biological activities with poor water solubility which limits its clinical development. In this study, we successfully prepared a novel, self-assembled micelle based on Rebaudioside A (RA) for oral delivery of HSP with improved bioavailability and therapeutic effects. We found that RA and HSP could be formylated into nanomicelles with particle sizes of 4.541 nm ± 0.048 nm. HSP was readily encapsulated into RA micelles and this improved its water solubility (to 12.74 mg/mL ± 0.28 mg/mL). The MTT results showed that RA-HSP enhanced the cytotoxicity, the clonal formation inhibitory activity, and cell migration inhibitory activity of HSP in human breast cancer MDA-MB-231 cells. The mechanism results showed that RA-HSP induced cell apoptosis by inducing the production of reactive oxygen species (ROS), destroying the mitochondrial membrane potential (MMP), and inhibiting the PI3K/Akt signaling pathway. Moreover, RA-HSP enhanced the anticancer activity, increased the oral bioavailability and tissue distribution of HSP in vivo. Moreover, the mechanism studies in vivo found that HSP inhibited PI3K/Akt signaling pathway with low side effects. These findings indicate that RA micelle formulations have great potential in oral drug delivery systems for the delivery of hydrophobic drugs.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Diterpenos do Tipo Caurano/química , Portadores de Fármacos , Hesperidina/farmacologia , Nanopartículas , Administração Oral , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacocinética , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Feminino , Hesperidina/administração & dosagem , Hesperidina/química , Hesperidina/farmacocinética , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Micelas , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Solubilidade , Distribuição Tecidual , Carga Tumoral/efeitos dos fármacos
7.
Int J Nanomedicine ; 16: 2597-2613, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33833514

RESUMO

Introduction: Limited by tumor vascular barriers, restricted intratumoural T cell infiltration and nanoparticles accumulation remain major bottlenecks for anticancer therapy. Platelets are now known to maintain tumor vascular integrity. Therefore, inhibition of tumor-associated platelets may be an effective method to increase T cell infiltration and drug accumulation at tumor sites. Herein, we designed an ultrasound-responsive nitric oxide (NO) release nanosystem, SNO-HSA-PTX, which can release NO in response to ultrasound (US) irradiation, thereby inhibiting platelet function and opening the tumor vascular barrier, promoting drug accumulation and T cell infiltration. Methods: We evaluated the ability of SNO-HSA-PTX to release NO in response to US irradiation. We also tested the effect of SNO-HSA-PTX on platelet function. Plenty of studies including cytotoxicity, pharmacokinetics study, biodistribution, blood perfusion, T cell infiltration, in vivo antitumor efficacy and safety assessment were conducted to investigate the antitumor effect of SNO-HSA-PTX. Results: SNO-HSA-PTX with US irradiation inhibited tumor-associated platelets activation and induced openings in the tumor vascular barriers, which promoted the accumulation of SNO-HSA-PTX nanoparticles to the tumor sites. Meanwhile, the damaged vascular barriers allowed oxygen-carrying hemoglobin to infiltrate tumor regions, alleviating hypoxia of the tumor microenvironment. In addition, the intratumoral T cell infiltration was augmented, together with chemotherapy and NO therapy, which greatly inhibited tumor growth. Discussion: Our research designed a simple strategy to open the vascular barrier by inhibiting the tumor-associated platelets, which provide new ideas for anti-tumor treatment.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Linfócitos do Interstício Tumoral/imunologia , Nanopartículas/administração & dosagem , Óxido Nítrico/metabolismo , Compostos Nitrosos/química , Paclitaxel/farmacologia , Albumina Sérica Humana/química , Ondas Ultrassônicas , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Apoptose , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Paclitaxel/administração & dosagem , Paclitaxel/farmacocinética , Distribuição Tecidual , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cancer Med ; 10(9): 3068-3076, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33826243

RESUMO

BACKGROUND: Paclitaxel is dosed according to body surface area (BSA) but there is scant information on actual drug exposure in overweight and obese patients. METHODS: Early breast cancer patients receiving paclitaxel at 175 mg/m2 every 3 weeks, in two BMI groups (normal, 18-24.9 kg/m2 and overweight/obese, ≥25 kg/m2 , respectively), matched for age, serum albumin and bilirubin levels using minimization technique, were included. Sparse pharmacokinetic (PK) sampling was performed at 7 time points from 0 h until 24 h of starting paclitaxel in cycle 1. Paclitaxel concentration was measured using a validated LCMS/MS method. Covariate effect on paclitaxel PK was evaluated by population PK analysis using NONMEM software. RESULTS: Eighteen female patients each were enrolled in normal and overweight groups with mean BMI of 21.62 ± 2.06 and 28.16 ± 2.31 kg/m2 , mean BSA of 1.44 ± 0.11 and 1.69 ± 0.14 m2 and mean paclitaxel dose of 250 ± 18 and 293 ± 21 mg, respectively. Model predicted AUC and dose normalized AUC (mean ±SD) in the normal BMI versus overweight obese groups were 23 ± 11.0 µmol*h/L versus 25.7 ± 13.7 µmol*h/L (two-sample t-test p > 0.05) and 0.08 ± 0.04 (µmol*h/L)/ µmol versus 0.08 ± 0.04 (µmol*h/L)/ µmol (2-sample t-test p > 0.05), respectively. No significant correlation was observed between BMI and standardized dose normalized AUC (Pearson's correlation coefficient, -0.009; p > 0.05). CONCLUSION: When dosed according to BSA calculated using actual body weight there is no significant difference in paclitaxel exposure between normal and overweight women. Using alternative descriptors of weight to calculate BSA could lead to under-dosing of this drug. TRIAL REGISTRATION: This study is registered in the Clinical Trials Registry of India CTRI/2015/09/006193.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Índice de Massa Corporal , Neoplasias da Mama/metabolismo , Paclitaxel/farmacocinética , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Área Sob a Curva , Peso Corporal , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Esquema de Medicação , Feminino , Humanos , Pessoa de Meia-Idade , Obesidade/metabolismo , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Sobrepeso/metabolismo , Paclitaxel/administração & dosagem , Estudos Prospectivos , Fatores de Tempo
9.
J Med Chem ; 64(7): 3677-3693, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33729781

RESUMO

Many chemotherapeutics, such as paclitaxel, are administered intravenously as they suffer from poor oral bioavailability, partly because of efflux mechanism of P-glycoprotein in the intestinal epithelium. To date, no drug has been approved by the U.S. Food and Drug Administration (FDA) that selectively blocks this efflux pump. We sought to identify a compound that selectively inhibits P-glycoprotein in the gastrointestinal mucosa with poor oral bioavailability, thus eliminating the issues such as bone marrow toxicity associated with systemic inhibition of P-glycoprotein. Here, we describe the discovery of highly potent, selective, and poorly orally bioavailable P-glycoprotein inhibitor 14 (encequidar). Clinically, encequidar was found to be well tolerated and minimally absorbed; and importantly, it enabled the oral delivery of paclitaxel.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Tetrazóis/farmacologia , Administração Oral , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacologia , Descoberta de Drogas , Humanos , Mucosa Intestinal/efeitos dos fármacos , Estrutura Molecular , Paclitaxel/administração & dosagem , Paclitaxel/farmacologia , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/metabolismo
10.
AAPS PharmSciTech ; 22(3): 96, 2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33694067

RESUMO

Increasing the drug tumor-specific accumulation and controlling their release is considered one of the most effective ways to increase the efficacy of drugs. Here, we developed a vesicle system that can target hepatoma and release drugs rapidly within tumor cells. This non-ionic surfactant vesicle is biodegradable. Galactosylated stearate has been used to glycosylate the vesicles to achieve liver targeting; replacement of a portion (Chol:CHEMS = 1:1) of cholesterol by cholesteryl hemisuccinate (CHEMS) allows for a rapid release of drugs in an acidic environment. In vitro release experiments confirmed that galactose-modified pH-sensitive niosomes loaded with tanshinone IIA had excellent drug release performance in acid medium. In vitro experiments using ovarian cancer cells (A2780), colon cancer cells (HCT8), and hepatoma cell (Huh7, HepG2) confirmed that the preparation had specific targeting ability to hepatoma cells compared with free drugs, and this ability was dependent on the galactose content. Furthermore, the preparation also had a more substantial inhibitory effect on tumor cells, and subsequent apoptosis assays and cell cycle analyses further confirmed its enhanced anti-tumor effect. Results of pharmacokinetic experiments confirmed that the vesicle system could significantly extend the blood circulation time of tanshinone IIA, and the larger area under the curve indicated that the preparation had a better drug effect. Thus, the results of biodistribution experiments confirmed the in vivo liver targeting ability of this preparation. Niosomes designed in this manner are expected to be a safe and effective drug delivery system for liver cancer therapy.


Assuntos
Abietanos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Carcinoma Hepatocelular/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Galactose/administração & dosagem , Neoplasias Hepáticas/metabolismo , Abietanos/farmacocinética , Animais , Antineoplásicos Fitogênicos/farmacocinética , Carcinoma Hepatocelular/tratamento farmacológico , Linhagem Celular Tumoral , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Liberação Controlada de Fármacos/fisiologia , Galactose/farmacocinética , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Lipossomos , Neoplasias Hepáticas/tratamento farmacológico , Masculino , Camundongos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
11.
Life Sci ; 275: 119377, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33757771

RESUMO

AIMS: Silibinin offers potential anticancer effect with less aqueous solubility and high permeability. The present study aimed to develop biocompatible magnetic-core-based nanopolymeric carriers of poly (D, l-lactide-co-glycolic) acid (PLGA) encapsulated silibinin for the sustained release action on renal cancerous cell. MAIN METHODS: The synthesized iron oxide nanoparticles were prepared by precipitation method via encapsulation of silibinin in PLGA network using double emulsion method. The nanoparticle formulations were characterized for morphological, physicochemical properties (HRTEM, FTIR, Raman Spectroscopy and VSM), in vitro drug release and cytotoxicity study on kidney cancer cells (A-498). The safety of magnetic-core-based silibinin nanopolymeric carriers was conducted by i.v. administration at a dose of 50 mg/kg in mice. KEY FINDINGS: The mean particle size, zeta potential and % encapsulation efficiency of magnetic-core-based silibinin nanopolymeric carriers were found to be 285.9 ± 0.28 nm, -14.71 ± 0.15 mV and 84.76 ± 1.29%, respectively. The saturation magnetization of magnetic core and optimized nanoparticles were reported as 36.35 emu/g and 12.78 emu/g, respectively. HRTEM analyses revealed the spherical shapes of the particles with uniform size distribution. The in vitro release profile of silibinin from the nanoparticles exhibited a sustained delivery for 15 days and displayed better cytotoxicity against human kidney cancer cells (A-498) than silibinin. In vivo study showed the safety of magnetic-core-based silibinin nanopolymeric carriers in mice. SIGNIFICANCE: The magnetic-core-based silibinin nanopolymeric carriers will act as a potential carrier for targeted transportation of actives in cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Portadores de Fármacos , Neoplasias Renais/tratamento farmacológico , Nanopartículas de Magnetita , Silibina/uso terapêutico , Antineoplásicos Fitogênicos/administração & dosagem , Linhagem Celular Tumoral , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/efeitos adversos , Humanos , Nanopartículas de Magnetita/administração & dosagem , Nanopartículas de Magnetita/efeitos adversos , Silibina/administração & dosagem , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman
12.
Biochem Pharmacol ; 186: 114456, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33556340

RESUMO

Ovarian cancer is poorly treatable due, at least in part, to induced drug resistance to taxol- and cisplatin-based chemotherapy. Recent studies showed that ectopic overexpression of toll-like receptor 4 (TLR4) in ovarian cancer cells leads to upregulation of the androgen receptor (AR) and transactivation of taxol resistance genes, thereby causing chemoresistance. In the present study, we examined the signaling pathways involving TLR4 and interleukin 6 (IL-6) that enhance AR expression. Based on transcriptomic analysis, we show that IL-6 functions as a hub gene among the upregulated genes in taxol-treated TLR4-overexpressing ovarian cancer cells. Both the TLR4 activator taxol and IL-6 can induce AKT phosphorylation, whereas TLR4 knockdown or inhibition of the IL-6 signal transducer GP130 abrogates AKT activation. Furthermore, expression of AR and IL-6 is downregulated in TLR4-knockdown, taxol-resistant cells. In addition, TLR4 knockdown inhibits GP130 and IL-6 receptor alpha (IL6Rα) activities, indicating that TLR4 plays a critical role in IL-6 signaling. On the other hand, nuclear translocation of AR is induced by IL-6 treatment, whereas knockdown of endogenous IL-6 reduces AR and TLR4 expression in taxol-resistant ovarian cancer cells. These results indicate that TLR4 and IL-6 play a crucial role in AR gene regulation and function. We also identify interferon regulatory factor 1 (IRF1) as a downstream target of IL-6 signaling and as a regulator of AR expression. Moreover, analysis of clinical samples indicates that high IL-6 expression correlates with poor progression-free survival in ovarian cancer patients treated with taxol. Overall, our findings indicate that the TLR4/IL-6/IRF1 signaling axis represents a potential therapeutic target to overcome AR-based taxol resistance in ovarian cancer.


Assuntos
Fator Regulador 1 de Interferon/biossíntese , Interleucina-6/biossíntese , Neoplasias Ovarianas/metabolismo , Paclitaxel/administração & dosagem , Receptores Androgênicos/biossíntese , Receptor 4 Toll-Like/biossíntese , Antineoplásicos Fitogênicos/administração & dosagem , Biomarcadores Tumorais/biossíntese , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Fator Regulador 1 de Interferon/genética , Interleucina-6/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Receptores Androgênicos/genética , Receptor 4 Toll-Like/genética
13.
Gene ; 779: 145494, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33588036

RESUMO

Microalgae, one of the most important classes of biomass producers, can produce exopolysaccharides similar to bacteria. The exopolysaccharide from Chlorella (CEPS) displays remarkable anticancer activity the mechanism of which remains to be elucidated. In this study, we analyzed the inhibitory effect of CEPS on the growth of HeLa cells. The results showed that CEPS inhibited the proliferation, decreased the viability, and changed the morphology of HeLa cells. Transcriptome analysis showed that 1894 genes were differentially expressed in the CEPS-treated group compared with the control group, including 1076 genes that were upregulated and 818 genes that were downregulated. The results of gene function enrichment analysis showed that the differentially expressed genes (DEGs) were significantly enriched in apoptosis and tumor-related biological processes and participated in several cancer and apoptosisrelated signaling pathways, including the MAPK signaling pathway, TNF signaling pathway, and the PI3K-Akt signaling pathway. The protein-protein interaction network identified 13 DEGs including PTPN11, RSAD2, ISG15, IFIT1, MX2, IFIT2, OASL, OAS1, JUN, OAS2, XAF1, ISG20, and IRF9 as hub genes. Our results suggest that CEPS is a promising therapeutic drug for the follow-up interventional therapy of cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Chlorella/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Polissacarídeos/farmacologia , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Perfilação da Expressão Gênica/métodos , Células HeLa , Humanos , Fosfatidilinositol 3-Quinases/genética , Polissacarídeos/administração & dosagem , Polissacarídeos/química , Mapas de Interação de Proteínas/efeitos dos fármacos , Mapas de Interação de Proteínas/genética , Células Vero
14.
Nutrients ; 13(2)2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540724

RESUMO

Juicing vegetables is thought to be an anticancer treatment. Support exists for a rank order of anticancer greens (kale > dandelion > lettuce > spinach) based on degrees of bioavailability of different phytochemicals, also offset by some noxious molecules (i.e., calcium-oxalate). We developed a new in vitro transepithelial anti-neuroblastoma model system. The juices were diluted as predicted once in the small intestine. They were applied to apical Caco-2Bbe1 cells atop dividing SH-SY5Y neuroblastoma cells, and changes in transepithelial electrical resistance (TEER) and cell growth were considered with juice spectroscopies. Studied first in monoculture, kale and dandelion were the most cytostatic juices on SH-SY5Ys, lettuce showed no effect, and high (4.2%) spinach was cytotoxic. In co-culture, high (4.2%) kale was quickest (three days) to inhibit neuroblastoma growth. By five days, dandelion and kale were equally robust. Lettuce showed small anti-proliferative effects at five days and spinach remained cytotoxic. Spinach's cytotoxicity corresponded with major infrared bands indicative of oxalate. Kale juice uniquely induced reactive oxygen species and S-phase cell cycle arrest in SH-SY5Y. The superiority of kale and dandelion was also apparent on the epithelium, because raising TEER levels is considered healthy. Kale's unique features corresponded with a major fluorescent peak that co-eluted with kaempferol during high performance liquid chromatography. Because the anticancer rank order was upheld, the model appears validated for screening anticancer juices.


Assuntos
Brassica/química , Técnicas de Cocultura , Neuroblastoma/tratamento farmacológico , Compostos Fitoquímicos/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Disponibilidade Biológica , Células CACO-2 , Linhagem Celular Tumoral , Impedância Elétrica , Epitélio/efeitos dos fármacos , Epitélio/fisiopatologia , Sucos de Frutas e Vegetais , Humanos , Spinacia oleracea/química , Taraxacum/química
15.
Medicine (Baltimore) ; 100(7): e24795, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33607838

RESUMO

RATIONALE: Ramucirumab, a human Ig 1 monoclonal antibody against vascular endothelial growth factor receptor-2, in combination with paclitaxel is a second-line chemotherapy for patients with metastatic gastric cancer. Several reports have suggested that dose adjustments of cetuximab, an anti- epidermal growth factor receptor antibody, are not required in patients with renal impairment. However, the combination chemotherapy of ramucirumab and cytotoxic drug for hemodialysis (HD) patients has not been reported. PATIENT CONCERNS: A 65-year-old man on HD was diagnosed with gastric cancer and underwent a subtotal gastrectomy with D2 lymphadenectomy. Abdominal computed tomography (CT) was examined after completion of 8 cycles of adjuvant chemotherapy with capecitabine combination oxaliplatin. DIAGNOSIS: The patient was diagnosed with advanced gastric cancer at stage IIIb (pT3N2M0) 11 months ago. Unfortunately, 9 months after the start of adjuvant chemotherapy, multiple liver metastases from gastric cancer were found by abdominal CT. INTERVENTIONS: He began receiving weekly paclitaxel(80 mg/m2) and every 15-day ramucirumab (8 mg/kg). HD was performed next day after administration of chemotherapy and repeated 3 times a week. OUTCOMES: He was treated with ramucirumab without dose adjustment. The metastatic liver mass had a partial response, after 2 and 4 cycles of chemotherapy and had a stable disease up to 12 cycles of chemotherapy. No obvious adverse effect was observed during treatment. However, after 14 cycles chemotherapy, follow-up abdominal CT revealed progression disease of multiple liver metastasis and lymph nodes invasion. LESSONS: The paclitaxel chemotherapy with ramucirumab is effective and safe in HD patients with metastatic gastric cancer. As seen in patients with normal kidney function, ramucirumab can be safely administered without a dose reduction.


Assuntos
Adenocarcinoma/secundário , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias Hepáticas/secundário , Paclitaxel/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Masculino , Diálise Renal , Neoplasias Gástricas/complicações , Tomografia Computadorizada por Raios X
16.
ACS Appl Mater Interfaces ; 13(4): 4853-4860, 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33474938

RESUMO

In our pervious study, a dual-functional peptide R7 was developed to form a complex with paclitaxel (PTX) for enhancement of PTX translocation. However, because of the unstable noncovalent bond between R7 and PTX, PTX redistributed after the introduction of heparin, leading to R7-PTX complex dissociation, further causing less PTX penetration than expected. Thus, a novel positive CPP carrier of P9 was developed to improve CPP-PTX affinity via a double-proline (Pro, P) hairpin tail and enhance PTX translocation through the reduction of translocation energy barrier, confirmed by the MM-PBSA analysis and umbrella sampling simulation. Cellular uptake study reveals that P9 can quickly translocate into the HeLa cells within 1 min and exhibits no noticeable cytotoxicity. Compared to R7, P9 is able to help PTX translocation, leading to a remarkable increase in the intracellular concentration of PTX, eventually resulting in a significant loss in tumor cell viability. In vivo experiments demonstrate that a vein injection of P9-PTX complex dramatically inhibits tumor growth. Our study provides a novel perspective for designing CPP-facilitated drug carrier to enhance antitumor efficiency.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Peptídeos Penetradores de Células/química , Portadores de Fármacos/química , Paclitaxel/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Dinâmica Molecular , Paclitaxel/farmacocinética , Paclitaxel/farmacologia
17.
ACS Appl Mater Interfaces ; 13(2): 2988-2996, 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33403846

RESUMO

Hollow graphene oxide microcapsules (GOMs) have been widely used in energy, electronics, catalysis, sensing, tissue engineering, and drug loading due to their unique properties. However, it is still a great challenge to prepare GOMs with high quality and in large quantity using a simple method. In this work, we obtained single-component GOMs using the liquid nitrogen cavitation effect, which directed the self-assembly of graphene oxide (GO) debris at the gas-liquid interface. This method avoids the introduction of additional components and removal of templates. The morphology of GOM with wrinkles on its surface was characterized by transmission electron microscopy and scanning electron microscopy. The abundant polar groups of GO microcapsules enabled them to easily disperse in water. Based on this, GOMs have good potential for loading hydrophobic drugs. Subsequently, we used GOMs as carriers to deliver a hydrophobic drug paclitaxel (PTX), which exhibited a good loading capacity. Moreover, PTX loaded GOMs showed excellent cytotoxicity to A549 and MDA-MB-231 cells. The GOMs also showed a pH-dependent drug release performance. Therefore, GOMs can be regarded as potential carriers for biomedical applications.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Portadores de Fármacos/química , Grafite/química , Paclitaxel/administração & dosagem , Células A549 , Antineoplásicos Fitogênicos/farmacocinética , Cápsulas/química , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Paclitaxel/farmacocinética , Água/química
18.
Food Chem Toxicol ; 149: 111960, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33385512

RESUMO

Erianin (ER), a dietary compound extracted from Dendrobium, a traditional Chinese medicinal edible herb, is well recognized for its potential anti-cancer activity. Nevertheless, its limitations, regarding its complex isolation procedure, low yield and low water solubility, limit large scale application. Combinatorial therapeutic regimen that combines several drugs to target different pathways in a characteristically synergistic manner at lower doses of drugs proved effective in several diseases treatment. Besides, new knowledge aimed at improving drug delivery into the intracellular environment is essential. In this study, ER was assessed for its cytotoxic effect in combination with doxorubicin hydrochloride (DOX·HCl) against breast cancer cells. Drug synergy was calculated by using combination index (CI) index and we discovered that they had positive effects. To ensure uniform delivery of both drugs to cells for a desired synergistic action, a dual drug loaded liposomes was developed using thin-film dispersion, and coated by a layer of folate-chitosan. Cytotoxicity and cell proliferation based assays revealed the increase of cell inhibition rate by more than 30% compared with free drugs. Fluorescence imaging revealed that liposomes can aid faster drugs accumulate in cancer cells. The study presented a novel strategy for the treatment of breast cancer.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Bibenzilas/farmacologia , Neoplasias da Mama/tratamento farmacológico , Sobrevivência Celular/efeitos dos fármacos , Dendrobium/química , Doxorrubicina/farmacologia , Fenol/farmacologia , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Bibenzilas/administração & dosagem , Bibenzilas/química , Linhagem Celular Tumoral , Dietética , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas , Feminino , Humanos , Lipossomos , Fenol/administração & dosagem , Fenol/química
19.
AAPS PharmSciTech ; 22(2): 56, 2021 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-33486601

RESUMO

Compared with single micelle, the new PTX-HS15/T80 mixed micelle system (PTX-HS15/T80 MMs) had achieved better results in solubilization, stability, and sensitization before. Therefore, we intend to further verify the potential advantages of the mixed micelle delivery system through in vitro cytotoxicity test and animal test to understand the anticancer effect and in vivo pharmaceutical behavior of the system. In vitro cytotoxicity test showed that the new PTX-HS15/T80 MMs had a stronger ability to inhibit the proliferation of cancer cells. The results of in vivo pharmacokinetics showed that the micelle had shorter half-life, higher clearance rate, and lower blood concentration and had good blood clearance characteristics. The results of in vivo tissue distribution showed that, compared with the single micelle Taxol®, the new PTX-HS15/T80 MMs had good distribution characteristics in the lung (AUC (lung 0-4 H) increased about 26%) and low concentration in the heart (AUC (Heart 0-4 H) decreased about 10%). Paclitaxel was mainly metabolized through the liver and kidney. The above results suggested that the new PTX-HS15/T80 MMs may have a certain therapeutic potential against lung cancer and reduce the toxic and side effects. In general, the mixed micelle delivery system was not only simple and cheap to prepare but also had certain advantages in vitro and in vivo, indicating that the combination of surfactants provides a good choice for solving the problem of insoluble drug delivery.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Micelas , Paclitaxel/administração & dosagem , Polietilenoglicóis/química , Polissorbatos/química , Ácidos Esteáricos/química , Animais , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Feminino , Masculino , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
20.
Pediatr Hematol Oncol ; 38(3): 208-215, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33150845

RESUMO

The objective of this study was to describe hypersensitivity reactions with and without the use of in-line filters during intravenous etoposide therapy in pediatric oncology patients. This was a retrospective review of all patients treated in the Division of Oncology/Hematology/Bone Marrow Transplant at British Columbia Children's Hospital with intravenous etoposide between December 1, 2013 and February 1, 2018. Hypersensitivity reactions and anaphylaxis associated with etoposide infusions were compared over time, including 12 months prior to, 27 months during the use of, and for 12 months after the discontinuation of in-line filtration. There were 192 patients (median age 6.0 (IQR 2.8-13.0) years treated with etoposide and 486 etoposide infusions including 137 (28%) before, 261 (54%) during and 88 (18%) after use of in-line filters at our center. Twenty-six of 486 (5%) and 13/486 (3%) of infusions resulted in a type I hypersensitivity reaction and anaphylaxis, respectively. There were 2/137 (1%), 36/261 (14%) and 1/88 (1%) infusion reactions prior to, during and after in-line filter use, respectively. Infusion reactions during the in-line filter period were higher than during the pre-filter (Z = 3.978; p < 0.001) and post-filter (Z = 3.335; p < 0.001) periods of the study. These data suggest that the use of in-line filtration may be associated with increased frequency of hypersensitivity reactions to etoposide in pediatric cancer patients.


Assuntos
Anafilaxia/induzido quimicamente , Antineoplásicos Fitogênicos/efeitos adversos , Etoposídeo/efeitos adversos , Hipersensibilidade Imediata/induzido quimicamente , Inibidores da Topoisomerase II/efeitos adversos , Antineoplásicos Fitogênicos/administração & dosagem , Criança , Pré-Escolar , Etoposídeo/administração & dosagem , Feminino , Filtração/instrumentação , Humanos , Infusões Intravenosas/instrumentação , Masculino , Estudos Retrospectivos , Inibidores da Topoisomerase II/administração & dosagem
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