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ACS Appl Mater Interfaces ; 11(11): 10578-10588, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30802029


Hepatocellular carcinoma (HCC) poses a great threat to human health. The elegant combination of gene therapy and chemotherapy by nanocarriers has been repeatedly highlighted to realize enhanced therapeutic efficacy relative to monotreatment. However, the leading strategy to achieve the efficient codelivery of the gene and drug remains the electrostatic condensation with the nucleic acid and the hydrophobic encapsulation of drug molecules by the nanocarriers, which suffers substantially from premature drug leakage during circulation and severe off-target-associated side effects. To address these issues, we reported in this study the codelivery of liver-specific miRNA-122 and anti-cancer drug 5-fluorouracil (5-Fu) using a macromolecular prodrug approach, that is, electrostatic condensation with miRNA-122 using galactosylated-chitosan-5-fluorouracil (GC-FU). The delivery efficacy was evaluated comprehensively in vitro and in vivo. Specifically, the biocompatibility of GC-FU/miR-122 nanoparticles (NPs) was assessed by hemolysis activity analysis, BSA adsorption test, and cell viability assay in both normal liver cells (L02 cells) and endothelial cells. The resulting codelivery systems showed enhanced blood and salt stability, efficient proliferation inhibition of HCC cells, and further induction apoptosis of HCC cells, as well as downregulated expression of ADAM17 and Bcl-2. The strategy developed herein is thus a highly promising platform for an effective codelivery of miRNA-122 and 5-Fu with facile fabrication and great potential for the clinical translation toward HCC synergistic therapy.

Materiais Biocompatíveis/química , MicroRNAs/metabolismo , Pró-Fármacos/química , Proteína ADAM17/metabolismo , Animais , Apoptose/efeitos dos fármacos , Materiais Biocompatíveis/farmacologia , Materiais Biocompatíveis/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Linhagem Celular , Quitosana/química , Regulação para Baixo/efeitos dos fármacos , Portadores de Fármacos/química , Sinergismo Farmacológico , Fluoruracila/química , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Hemólise/efeitos dos fármacos , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/química , Nanopartículas/química , Nanopartículas/toxicidade , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico
Artif Cells Nanomed Biotechnol ; 46(sup3): S661-S670, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30307317


Hepatocellular carcinoma (HCC) is one of the greatest public health problems worldwide, and chemotherapy remains the major approach for the HCC treatment. Doxorubicin (DOX) is one of the anthracycline antibiotics but its clinical use is limited due to its severe cardiotoxicity. In this study, novel hybrid nanoparticles by self-assembling based on pectin-doxorubicin conjugates (PDC-NPs) were fabricated for HCC treatment. The stabilized structure of the PDC-NPs was characterized by methylene blue absorption, the size, zeta potential and the morphology, which was investigated by Zetasizer nanoparticle analyzer and transmission electron microscope (TEM), of nanoparticles. The PDC-NPs achieved a sustained and prolonged release ability, which was illustrated with in vitro drug release profiles, anti-cell proliferation study, cellular uptake assay and in vivo pharmacokinetics analysis. Biocompatibility of the PDC-NPs was assessed with bovine serum albumin (BSA) adsorption test, hemolysis activity examination and viability evaluation of human umbilical vein endothelial cells. Importantly, in vivo studies of the PDC-NPs, which were performed in the athymic BALB/c nude mice, demonstrated that the PDC-NPs significantly reduced the lethal side effect of DOX. Additionally, the H&E staining and serum biochemistry study further confirmed the excellent biological security of the PDC-NPs.

Carcinoma Hepatocelular , Doxorrubicina , Neoplasias Hepáticas , Nanopartículas , Pectinas , Animais , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico , Pectinas/química , Pectinas/farmacocinética , Pectinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto