N-Acetylgalactosamine-Targeted Delivery of Dendrimer-Doxorubicin Conjugates Influences Doxorubicin Cytotoxicity and Metabolic Profile in Hepatic Cancer Cells.
Adv Healthc Mater
; 6(5)2017 Mar.
Article
em En
| MEDLINE
| ID: mdl-28085993
ABSTRACT
This study describes the development of targeted, doxorubicin (DOX)-loaded generation 5 (G5) polyamidoamine dendrimers able to achieve cell-specific DOX delivery and release into the cytoplasm of hepatic cancer cells. G5 is functionalized with poly(ethylene glycol) (PEG) brushes displaying N-acetylgalactosamine (NAcGal) ligands to target hepatic cancer cells. DOX is attached to G5 through one of two aromatic azo-linkages, L3 or L4, achieving either P1 ((NAcGalß -PEGc)16.6 -G5-(L3-DOX)11.6 ) or P2 ((NAcGalß -PEGc)16.6 -G5-(L4-DOX)13.4 ) conjugates. After confirming the conjugates' biocompatibility, flow cytometry studies show P1/P2 achieve 100% uptake into hepatic cancer cells at 30-60 × 10-9 m particle concentration. This internalization correlates with cytotoxicity against HepG2 cells with 50% inhibitory concentration (IC50 ) values of 24.8, 1414.0, and 237.8 × 10-9 m for free DOX, P1, and P2, respectively. Differences in cytotoxicity prompted metabolomics analysis to identify the intracellular release behavior of DOX. Results show that P1/P2 release alternative DOX metabolites than free DOX. Stable isotope tracer studies show that the different metabolites induce different effects on metabolic cycles. Namely, free DOX reduces glycolysis and increases fatty acid oxidation, while P1/P2 increase glycolysis, likely as a response to high oxidative stress. Overall, P1/P2 conjugates offer a platform drug delivery technology for improving hepatic cancer therapy.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Acetilgalactosamina
/
Doxorrubicina
/
Sistemas de Liberação de Medicamentos
/
Dendrímeros
/
Neoplasias Hepáticas
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article