Evidence map›Paper›PMID 34983554›Full record

ArticleJournal of nanobiotechnology2022

Nano delivery of simvastatin targets liver sinusoidal endothelial cells to remodel tumor microenvironment for hepatocellular carcinoma.

Zhuo Yu, Jianfeng Guo, Yun Liu, Menglin Wang, Zhengsheng Liu, Yueqiu Gao, Leaf Huang

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of nanobiotechnology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
61citing papers in PubMed, 2 pooled it
15.0field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

61 citing papers in PubMed, 2 syntheses or guidelines pooled it, 99 citations in OpenAlex.

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  15. Targeted nano-drug delivery systems for tumor immunotherapy.Journal of pharmaceutical analysis · 2026
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1 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 2 institutions in 2 countries.

Zhuo YuDivision of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA.ORCID http://orcid.org/0000-0003-4100-8415
Jianfeng GuoDivision of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA.
Yun LiuDivision of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA.
Menglin WangDivision of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA.
Zhengsheng LiuDivision of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA.
Yueqiu GaoDepartment of Liver Disease, Shuguang Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China. gaoyueqiu@shutcm.edu.cn.
Leaf HuangDivision of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599, USA. leafh@email.unc.edu.
University of North Carolina at Chapel Hill · USShanghai University of Traditional Chinese Medicine · CN

Funding

Small Animal Imaging CoreU54CA198999 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI LI, ZIBO · 2015 to 2019
$11.9M
NCI NIH HHS U54 CA198999NIH HHS CA198999
6 · The paper itself

Abstract

backgroundHepatocellular carcinoma (HCC) developed in fibrotic liver does not respond well to immunotherapy, mainly due to the stromal microenvironment and the fibrosis-related immunosuppressive factors. The characteristic of liver sinusoidal endothelial cells (LSECs) in contributing to fibrosis and orchestrating immune response is responsible for the refractory to targeted therapy or immunotherapy of HCC. We aim to seek a new strategy for HCC treatment based on an old drug simvastatin which shows protecting effect on LSEC.

methodThe features of LSECs in mouse fibrotic HCC model and human HCC patients were identified by immunofluorescence and scanning electron microscopy. The effect of simvastatin on LSECs and hepatic stellate cells (HSCs) was examined by immunoblotting, quantitative RT-PCR and RNA-seq. LSEC-targeted delivery of simvastatin was designed using nanotechnology. The anti-HCC effect and toxicity of the nano-drug was evaluated in both intra-hepatic and hemi-splenic inoculated mouse fibrotic HCC model.

resultsLSEC capillarization is associated with fibrotic HCC progression and poor survival in both murine HCC model and HCC patients. We further found simvastatin restores the quiescence of activated hepatic stellate cells (aHSCs) via stimulation of KLF2-NO signaling in LSECs, and up-regulates the expression of CXCL16 in LSECs. In intrahepatic inoculated fibrotic HCC mouse model, LSEC-targeted nano-delivery of simvastatin not only alleviates LSEC capillarization to regress the stromal microenvironment, but also recruits natural killer T (NKT) cells through CXCL16 to suppress tumor progression. Together with anti-programmed death-1-ligand-1 (anti-PD-L1) antibody, targeted-delivery of simvastatin achieves an improved therapeutic effect in hemi-splenic inoculated advanced-stage HCC model.

conclusionsThese findings reveal an immune-based therapeutic mechanism of simvastatin for remodeling immunosuppressive tumor microenvironment, therefore providing a novel strategy in treating HCC.

Indexed as

Carcinoma, HepatocellularLiver NeoplasmsNanoparticle Drug Delivery SystemAnimalsCells, CulturedEndothelial CellsHepatic Stellate CellsHumansLiverMaleMiceMice, Inbred C57BLNanoparticlesSignal TransductionSimvastatinTumor MicroenvironmentNanoparticle Drug Delivery SystemSimvastatinHepatocellular carcinomaLiver sinusoidal endothelial cellsNanoparticlesSimvastatinTumor microenvironment remodeling

Identifiers

PMID34983554
PMCPMC8725360
OpenAlexW4205834838

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.