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Mol Pharm ; 15(7): 2594-2605, 2018 07 02.
Artículo en Inglés | MEDLINE | ID: mdl-29763568

RESUMEN

We previously developed a new zinc(II) phthalocyanine (ZnPc) derivative (Pc 1) conjugated to poly-L-glutamic acid (PGA) (1-PG) to address the limitations of ZnPc as part of an antitumor photodynamic therapy approach, which include hydrophobicity, phototoxicity, and nonselectivity in biodistribution and tumor targeting. During this study, we discovered that 1-PG possessed high near-infrared (NIR) light absorptivity (λmax = 675 nm), good singlet oxygen generation efficiency in an aqueous environment, and enhanced photocytotoxic efficacy and cancer cell uptake in vitro. In the current study, we discovered that 1-PG accumulated in 4T1 mouse mammary tumors, with a retention time of up to 48 h. Furthermore, as part of an antitumor PDT, low dose 1-PG (2 mg of Pc 1 equivalent/kg) induced a greater tumor volume reduction (-74 ± 5%) when compared to high dose ZnPc (8 mg/kg, -50 ± 12%). At higher treatment doses (8 mg of Pc 1 equivalent/kg), 1-PG reduced tumor volume maximally (-91 ± 6%) and suppressed tumor size to a minimal level for up to 15 days. The kidney, liver, and lungs of the mice treated with 1-PG (both low and high doses) were free from 4T1 tumor metastasis at the end of the study. Telemetry-spectral-echocardiography studies also revealed that PGA (65 mg/kg) produced insignificant changes to the cardiovascular physiology of Wistar-Kyoto rats when administered in vivo. Results indicate that PGA displays an excellent cardiovascular safety profile, underlining its suitability for application as a nanodrug carrier in vivo. These current findings indicate the potential of 1-PG as a useful photosensitizer candidate for clinical PDT.


Asunto(s)
Indoles/administración & dosificación , Nanoconjugados/química , Neoplasias/tratamiento farmacológico , Compuestos Organometálicos/administración & dosificación , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/administración & dosificación , Animales , Cardiotoxicidad/diagnóstico por imagen , Cardiotoxicidad/etiología , Línea Celular Tumoral/trasplante , Modelos Animales de Enfermedad , Ensayos de Selección de Medicamentos Antitumorales , Ecocardiografía , Humanos , Indoles/efectos adversos , Indoles/farmacocinética , Masculino , Ratones , Ratones Endogámicos BALB C , Neoplasias/patología , Compuestos Organometálicos/efectos adversos , Compuestos Organometálicos/farmacocinética , Fotoquimioterapia/efectos adversos , Fármacos Fotosensibilizantes/efectos adversos , Fármacos Fotosensibilizantes/farmacocinética , Ácido Poliglutámico/química , Ratas , Ratas Endogámicas WKY , Distribución Tisular
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