Nanoparticle formulation of mycophenolate mofetil achieves enhanced efficacy against hepatocellular carcinoma by targeting tumour-associated fibroblast.
J Cell Mol Med
; 25(7): 3511-3523, 2021 04.
Article
em En
| MEDLINE
| ID: mdl-33713546
ABSTRACT
Hepatocellular carcinoma (HCC) is one of the most aggressive tumours with marked fibrosis. Mycophenolate mofetil (MMF) was well-established to have antitumour and anti-fibrotic properties. To overcome the poor bioavailability of MMF, this study constructed two MMF nanosystems, MMF-LA@DSPE-PEG and MMF-LA@PEG-PLA, by covalently conjugating linoleic acid (LA) to MMF and then loading the conjugate into polymer materials, PEG5k -PLA8k and DSPE- PEG2k , respectively. Hepatocellular carcinoma cell lines and C57BL/6 xenograft model were used to examine the anti-HCC efficacy of nanoparticles (NPs), whereas NIH-3T3 fibroblasts and highly-fibrotic HCC models were used to explore the anti-fibrotic efficacy. Administration of NPs dramatically inhibited the proliferation of HCC cells and fibroblasts in vitro. Animal experiments revealed that MMF-LA@DSPE-PEG achieved significantly higher anti-HCC efficacy than free MMF and MMF-LA@PEG-PLA both in C57BL/6 HCC model and highly-fibrotic HCC models. Immunohistochemistry further confirmed that MMF-LA@DSPE-PEG dramatically reduced cancer-associated fibroblast (CAF) density in tumours, as the expression levels of alpha-smooth muscle actin (α-SMA), fibroblast activation protein (FAP) and collagen IV were significantly downregulated. In addition, we found the presence of CAF strongly correlated with increased HCC recurrence risk after liver transplantation. MMF-LA@DSPE-PEG might act as a rational therapeutic strategy in treating HCC and preventing post-transplant HCC recurrence.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sistemas de Liberação de Medicamentos
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Carcinoma Hepatocelular
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Composição de Medicamentos
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Nanopartículas
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Ácido Micofenólico
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article