RESUMEN
Colon carcinoma is one of the common malignant tumors and has high morbidity and mortality in the world. Pigment epithelial-derived factor (PEDF) has been found to be the most potent natural inhibitor of angiogenesis and PEDF gene has been extensively used for the therapy of tumors, which suggests a potential approach to the therapy of colon carcinoma. However, the transfer of PEDF gene largely depends on the effective gene delivery systems. Poly (lactic-co-glycolic acid) nanoparticles (PLGANPs) have been extensively used for gene therapy due to its low-toxicity, biocompatibility and biodegradability, due to its potential to be an excellent carrier of the PEDF gene. We investigated the effect of PEDF gene loaded in PLGA nanoparticles (PEDF-PLGANPs) on the mouse colon carcinoma cells (CT26s) in vitro and in vivo. Blank PLGANPs (bPLGANPs) showed lower cytotoxicity than PEI to the CT26s. In vitro, PEDF-PLGANPs directly induced CT26 apoptosis and inhibit human umbilical vein endothelial cell (HUVEC) proliferation. In vivo, PEDF-PLGANPs inhibited CT26 tumors growth by inducing CT26 apoptosis, decreasing MVD and inhibiting angiogenesis. Our present study demonstrates the inhibitory effect of PEDF-PLGANPs on the growth of CT26s in vitro and in vivo for the first time. PLGANP-mediated PEDF gene could provide an innovative strategy for the therapy of colon carcinoma.
Asunto(s)
Carcinoma/terapia , Neoplasias del Colon/terapia , Proteínas del Ojo/genética , Técnicas de Transferencia de Gen , Terapia Genética/métodos , Ácido Láctico/química , Nanopartículas , Factores de Crecimiento Nervioso/genética , Ácido Poliglicólico/química , Serpinas/genética , Animales , Apoptosis/efectos de los fármacos , Carcinoma/irrigación sanguínea , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/irrigación sanguínea , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Dependovirus/genética , Células Endoteliales/efectos de los fármacos , Proteínas del Ojo/biosíntesis , Vectores Genéticos , Humanos , Ácido Láctico/toxicidad , Ratones , Ratones Endogámicos BALB C , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Neovascularización Patológica/prevención & control , Factores de Crecimiento Nervioso/biosíntesis , Ácido Poliglicólico/toxicidad , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Serpinas/biosíntesis , Factores de Tiempo , Carga Tumoral/efectos de los fármacosRESUMEN
Multidrug resistant (MDR) cancer may be treated using combinations of encapsulated cytotoxic drugs and chemosensitizers. To optimize the effectiveness of this combinational approach, poly(d,l-lactide-co-glycolide acid) (PLGA) nanoparticles formulations capable of delivering a cytotoxic drug, vincristine, a chemosensitizer, verapamil, or their combination were prepared via combining O/W emulsion solvent evaporation and salting-out method. Moreover, this work evaluated a number of approaches for the administration of chemosensitizer-cytotoxic drug combinations in a systematic fashion. The results showed that the administration sequence of anticancer drug and chemosensitizer was critical for maximal therapeutic efficacy and the simultaneous administration of vincristine and verapamil could achieve the highest reversal efficacy. In addition, PLGA nanoparticles (PLGANPs) showed moderate MDR reversal activity on MCF-7/ADR cells resistant to vincristine. The dual-agent loaded PLGA nanoparticles system resulted in the similar cytotoxicity to one free drug/another agent loaded PLGANPs combination and co-administration of two single-agent loaded PLGANPs, which was slightly higher than that of the free vincristine/verapamil combination. Co-encapsulation of anticancer drug and chemosensitizer might cause lower normal tissue drug toxicity and fewer drug-drug interactions. Therefore, we speculate that PLGANPs simultaneously loaded with anticancer drug and chemosensitizer might be the most potential formulation in the treatment of drug resistant cancers in vivo.