RESUMEN
5-Fluorouracil (5-FU) is used as a standard first-line drug for colorectal cancer malignancy (CRC), but it brings a series of side effects such as severe diarrhea and intestinal damage. Our previous study found that a large number of senescent cells increased while 5-Fu induced intestinal damage, and anti-senescence drugs can alleviate its side effects of inflammatory damage. Oleanolic acid (OA) is a common pentacyclic triterpenoid mainly derived from food fungi and medicinal plants, and studies have shown that it mainly possesses hepatoprotective, enzyme-lowering, anti-inflammatory, and anti-tumor effects. But its role in senescence is still unclear. In the present study, we demonstrated for the first time that OA ameliorated 5-Fu-induced human umbilical vein endothelial cells (HUVECs) and human normal intestinal epithelial cells (NCM460) in a 5-Fu-induced cellular senescence model by decreasing the activity of SA-ß-gal-positive cells, and the expression of senescence-associated proteins (p16), senescence-associated genes (p53 and p21), and senescence-associated secretory phenotypes (SASPs: IL-1ß, IL-6, IL-8, IFN-γ and TNF-α). Meanwhile, in this study, in a BALB/c mouse model, we demonstrated that 5-FU induced intestinal inflammatory response and injury, which was also found to be closely related to the increase of senescent cells, and that OA treatment was effective in ameliorating these adverse phenomena. Furthermore, our in vivo and in vitro studies showed that OA could alleviate senescence by inhibiting mTOR. In colon cancer cell models, OA also enhanced the ability of 5-FU to kill HCT116 cells and SW480 cells. Overall, this study demonstrates for the first time the potential role of OA in counteracting the side effects of 5-FU chemotherapy, providing a new option for the treatment of colorectal cancer to progressively achieve the goal of high efficacy and low toxicity of chemotherapy.
Asunto(s)
Senescencia Celular , Fluorouracilo , Células Endoteliales de la Vena Umbilical Humana , Inflamación , Ácido Oleanólico , Ácido Oleanólico/farmacología , Fluorouracilo/efectos adversos , Fluorouracilo/farmacología , Humanos , Senescencia Celular/efectos de los fármacos , Animales , Ratones , Inflamación/tratamiento farmacológico , Inflamación/patología , Inflamación/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Ratones Endogámicos BALB C , Intestinos/efectos de los fármacos , Intestinos/patología , Masculino , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patologíaRESUMEN
In the present study, we prepared NGR-modified sterically stabilized liposomes containing paclitaxel (NGR-SSL-PTX) in order to evaluate their potential targeting to aminopeptidase N receptors expressed on tumor endothelial cells and the tumor cell surface and its anti-angiogenic activity following metronomic administration. NGR-SSL-PTX was prepared by a thin-film hydration method. The in vitro targeting characteristics of NGR-modified liposomes on HUVEC (human umbilical vein endothelial cells), HT1080 (human ï¬brosarcoma cells) and MCF-7 (human breast adenocarcinoma cells) were then investigated. The effect of NGR-SSL-PTX on HUVEC proliferation and migration was also tested. The pharmacokinetics of NGR-SSL-PTX was studied in rats. The in vivo targeting activity of NGR-modified liposomes was investigated in HT1080 tumor-bearing mice. The anti-tumor activity of NGR-SSL-PTX following metronomic administration was evaluated in HT1080 tumor-bearing mice in vivo. The targeting activity of the NGR-modified liposomes was demonstrated by in vitro flow cytometry and confocal microscopy as well as in vivo confocal immunofluorescence microscopy and bio-distribution experiments. The results of endothelial cell proliferation and migration and microvessel density (MVD) confirmed the anti-angiogenic activity of NGR-SSL-PTX in vitro and in vivo. The sustained circulation of NGR-SSL-PTX was shown in the pharmacokinetic study. NGR-SSL-PTX is able to improve treatment efficacy producing the most significant anti-tumor activity and anti-angiogenic following metronomic administration.
Asunto(s)
Fibrosarcoma/tratamiento farmacológico , Fibrosarcoma/metabolismo , Liposomas/química , Nanocápsulas/administración & dosificación , Oligopéptidos/química , Paclitaxel/administración & dosificación , Paclitaxel/farmacocinética , Administración Metronómica , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacocinética , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacocinética , Difusión , Femenino , Fibrosarcoma/patología , Humanos , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanocápsulas/química , Especificidad de Órganos , Paclitaxel/química , Ratas , Ratas Sprague-Dawley , Distribución Tisular , Resultado del TratamientoRESUMEN
The acidic pH in tumor tissues could be used for targeting solid tumors. In the present study, we designed a tumor-specific pH-responsive peptide H(7)K(R(2))(2), which could respond to the acidic pH in tumor tissues, and prepared H(7)K(R(2))(2)-modified polymeric micelles containing paclitaxel (PTX-PM-H(7)K(R(2))(2)) in order to evaluate their potential targeting of tumor cells and tumor endothelial cells and their anti-tumor activity in mice with tumor cells. PTX-PM-H(7)K(R(2))(2) was prepared by a thin-film hydration method. The in vitro release of PTX from PTX-PM-H(7)K(R(2))(2) was tested. The in vitro targeting characteristics of H(7)K(R(2))(2)-modified polymeric micelles on HUVEC (human umbilical vein endothelial cells) and MCF-7 (human breast adenocarcinoma cells) were evaluated. The in vivo targeting activity of H(7)K(R(2))(2)-modified polymeric micelles and the in vivo anti-tumor activity of PTX-PM-H(7)K(R(2))(2) were also investigated in MCF-7 tumor-bearing mice. The released PTX from the PTX-PM-H(7)K(R(2))(2) was not affected by the pH. The targeting activity of the H(7)K(R(2))(2)-modified polymeric micelles was demonstrated by in vitro flow cytometry and confocal microscopy as well as in vivo biodistribution. PTX-PM-H(7)K(R(2))(2) produced very marked anti-tumor and anti-angiogenic activity in MCF-7 tumor-bearing mice in vivo.
Asunto(s)
Micelas , Neoplasias/patología , Paclitaxel/farmacología , Péptidos/química , Polímeros/química , Animales , Carbocianinas/metabolismo , Línea Celular , Proliferación Celular/efectos de los fármacos , Femenino , Citometría de Flujo , Humanos , Concentración de Iones de Hidrógeno/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Microscopía Confocal , Microscopía Electrónica de Transmisión , Microvasos/efectos de los fármacos , Microvasos/patología , Neoplasias/irrigación sanguínea , Neovascularización Patológica/patología , Paclitaxel/química , Tamaño de la Partícula , Distribución Tisular/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The purpose of the present study was to prepare a novel domperidone hydrogel. The domperidone dispersion was prepared by the solvent evaporation method. The characteristics of domperidone dispersion were measured by dynamic light scattering (DLS), scanning electronic microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffractometry, and solubility test, respectively. Domperidone hydrogel was prepared by directly incorporating the domperidone dispersion in Carbopol hydrogel to increase its mucoadhesive properties to gastrointestinal tract (GIT). The in vivo pharmacokinetic and pharmacodynamic studies were investigated to evaluate the relative oral bioavailability and the propulsion efficacy of domperidone hydrogel as compared with market domperidone tablet (Motilium tablet). The particle size of domperidone dispersion in distilled water was 454.0 nm. The results of DSC and X-ray indicated that domperidone in dispersion was in amorphous state. The solubility of domperidone in the dispersion in distilled water, pH of 1, 5, and 7 buffer solution was 45.7-, 63.9-, 13.1-, and 3.7-fold higher than that of raw domperidone, respectively. The area under the plasma concentration curve (AUC(0-24)) in domperidone hydrogel was 2.2-fold higher than that of tablet. The prolonged propulsion efficacy in the domperidone hydrogel group compared to that in tablet group was observed in the pharmacodynamic test.
RESUMEN
The purpose of this study was to prepare a novel paclitaxel (PTX) microemulsion containing a reduced amount of Cremophor EL (CrEL) which had similar pharmacokinetics and antitumor efficacy as the commercially available PTX injection, but a significantly reduced allergic effect due to the CrEL. The pharmacokinetics, biodistribution, in vivo antitumor activity and safety of PTX microemulsion was evaluated. The results of pharmacokinetic and distribution properties of PTX in the microemulsion were similar to those of the PTX injection. The antitumor efficacy of the PTX microemulsion in OVCRA-3 and A 549 tumor-bearing animals was similar to that of PTX injection. The PTX microemulsion did not cause haemolysis, erythrocyte agglutination or simulative reaction. The incidence and degree of allergic reactions exhibited by the PTX microemulsion group, with or without premedication, were significantly lower than those in the PTX injection group (P < .01). In conclusion, the PTX microemulsion had similar pharmacokinetics and anti-tumor efficacy to the PTX injection, but a significantly reduced allergic effect due to CrEL, indicating that the PTX microemulsion overcomes the disadvantages of the conventional PTX injection and is one way of avoiding the limitations of current injection product while providing suitable therapeutic efficacy.
Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Glicerol/análogos & derivados , Paclitaxel/química , Paclitaxel/farmacología , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/química , Perros , Emulsiones/efectos adversos , Emulsiones/química , Femenino , Glicerol/efectos adversos , Glicerol/química , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Paclitaxel/efectos adversos , Paclitaxel/farmacocinética , Tamaño de la Partícula , Vehículos Farmacéuticos/efectos adversos , Vehículos Farmacéuticos/química , Conejos , Ratas , Ratas Sprague-Dawley , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Aminopeptidase N (APN), recognized by Asn-Gly-Arg (NGR) peptides, is expressed in the pericytes associated with the BBB, and the main objective of this study is to confirm the hypothesis that NGR-modified DSPE-PEG micelles containing paclitaxel (NGR-M-PTX) can bind to and kill brain tumor angiogenic blood vessels and penetrate into the brain tumor interstitial space, resulting in direct cell death. NGR-M-PTX is prepared by a thin-film hydration method. The in vitro targeting characteristics of NGR-modified micelles on BMEC (murine brain microvascular endothelial cells) were investigated. The effect of NGR-M-PTX on BMEC proliferation and the cytotoxicity of NGR-M-PTX in C6 glioma cells were also tested. The antitumor activity NGR-M-PTX was evaluated in C6 glioma tumor-bearing rats in vivo. The particle size of NGR-M-PTX was approximately 54.2 nm. The drug encapsulation efficiency of NGR-M-PTX was 82.11 ± 2.82%. The cellular coumarin-6 level of NGR-M-coumarin-6 in the BMEC was about 2.2-fold higher than that of M-coumarin-6. BMEC proliferation was significantly inhibited by NGR-M-PTX. NGR-M-PTX had a much lower IC(50) value than M-PTX and free drug. The growth of C6 glioma tumor was markedly inhibited by NGR-M-PTX compared with Taxol. In conclusion, our results show that antiangiogenic therapy using NGR-M-PTX exhibits potent in vivo antitumor activity in a C6 glioma-bearing animal model.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Portadores de Fármacos/química , Glioma/tratamiento farmacológico , Oligopéptidos/química , Paclitaxel/uso terapéutico , Fosfatidiletanolaminas/química , Polietilenglicoles/química , Inhibidores de la Angiogénesis/administración & dosificación , Animales , Neoplasias Encefálicas/irrigación sanguínea , Neoplasias Encefálicas/enzimología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Células Endoteliales/efectos de los fármacos , Citometría de Flujo , Glioma/irrigación sanguínea , Glioma/enzimología , Glutamil Aminopeptidasa/metabolismo , Masculino , Ratones , Micelas , Microscopía Fluorescente , Trasplante de Neoplasias , Paclitaxel/administración & dosificación , Tamaño de la Partícula , Ratas , Ratas Sprague-DawleyRESUMEN
The purpose of this present study was to evaluate the antiangiogenic activity of sterically stabilized liposomes containing paclitaxel (SSL-PTX). The SSL-PTX was prepared by the thin-film method. The release of paclitaxel from SSL-PTX was analyzed using a dialysis method. The effect of SSL-PTX on endothelial cell proliferation and migration was investigated in vitro. The antitumor and antiangiogenic activity of SSL-PTX was evaluated in MDA-MB-231 tumor xenograft growth in BALB/c nude mice. The release of paclitaxel from SSL-PTX was 22% within 24 h. Our in vitro results indicated that SSL-PTX could effectively inhibit the endothelial cell proliferation and migration at a concentration-dependent manner. We also observed that metronomic SSL-PTX induced marked tumor growth inhibition in MDA-MB-231 xenograft model via the antiangiogenic mechanism, unlike that in paclitaxel injection (Taxol) formulated in Cremophor EL (CrEL). Overall, our results suggested that metronomic chemotherapy with low-dose, CrEL-free SSL-PTX should be feasible and effective.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Preparaciones de Acción Retardada/síntesis química , Liposomas/química , Paclitaxel/administración & dosificación , Paclitaxel/química , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/química , Animales , Neoplasias de la Mama/patología , Línea Celular Tumoral , Difusión , Composición de Medicamentos/métodos , Estabilidad de Medicamentos , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Resultado del TratamientoRESUMEN
Considering the effects of conjugated linoleic acid (CLA) on anti-tumor and anti-angiogenic in brain tumor, synergistic anti-tumor activity with taxane as well as potential activity for transporting chemotherapeutic agents across the blood-brain barrier (BBB), the purpose of this study was to synthesize CLA-paclitaxel (CLA-PTX) conjugate which could reach to the brain tissue and target brain tumor. The CLA was covalently linked to PTX. The conjugate was stable in PBS and rat plasma in vitro and had no microtubule assembly activity in solution and slight effect of arresting cell cycle progression at the G(2)-M phase. The in vitro cytotoxicity of conjugate was lower than that of PTX (p < 0.05). The conjugate showed higher cellular uptake efficiency on C6 glioma cells. The entire pharmacokinetic index revealed the significant enhancement of the conjugate pharmacokinetics compared with that in PTX (p < 0.01). The conjugate, unlike PTX, could distribute in brain tissue and retained higher concentrations throughout 360 h. The anti-tumor efficacy in brain tumor-bearing rats after administering conjugate was significantly higher than that after giving Taxol (p < 0.01). In conclusion, this CLA-PTX conjugate showed great potential to become a new prodrug of PTX and the methodology can be applied to other anticancer drugs.