1. Academic Validation
  2. Nanoparticle formulation of mycophenolate mofetil achieves enhanced efficacy against hepatocellular carcinoma by targeting tumour-associated fibroblast

Nanoparticle formulation of mycophenolate mofetil achieves enhanced efficacy against hepatocellular carcinoma by targeting tumour-associated fibroblast

  • J Cell Mol Med. 2021 Apr;25(7):3511-3523. doi: 10.1111/jcmm.16434.
Zhentao Yang 1 2 3 4 Liang Zhang 1 2 3 4 Hai Zhu 1 2 3 4 Ke Zhou 1 2 3 4 Hangxiang Wang 1 2 3 4 Yuchen Wang 2 3 4 Rong Su 2 3 4 Danjing Guo 2 3 4 Lin Zhou 1 2 3 4 Xiao Xu 1 2 3 4 Penghong Song 1 2 3 4 Shusen Zheng 1 2 3 4 Haiyang Xie 1 2 3 4
Affiliations

Affiliations

  • 1 Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Afliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 2 NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou, China.
  • 3 Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou, China.
  • 4 Key Laboratory of Organ Transplantation, Hangzhou, China.
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.

Keywords

cancer-associated fibroblast; hepatocellular carcinoma; mycophenolate mofetil; nanoparticles.

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