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
  • 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.
PMID: 33713546 DOI: 10.1111/jcmm.16434
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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