| dc.description.abstract | Introduction: Liver cancer is one of the most dangerous types of cancer today
and includes two types: primary and secondary. Primary cancer starts in the liver
tissue itself, while secondary cancer has metastasized to the liver from another
organ. Hepatocellular carcinoma (HCC) is known as the most common type of
cancer in adults and is currently one of the leading causes of death among people
with cirrhosis caused by hepatitis B or C. Current treatments include surgery and
chemotherapy, but these methods have many side effects and may reduce survival
rates. Therefore, researchers are trying to find alternative treatments with fewer
side effects and greater efficacy. One promising option in this regard is the use of
nanocarriers. Cellulose, a natural polymer material, has attracted much attention
in recent years in the field of drug delivery due to its properties such as
biocompatibility, biodegradability, and easy availability. The aim of this study is
to synthesize nanoparticles based on microcrystalline cellulose derivatives that
have the ability to load polyplexes containing miR-34a and 3MA and
simultaneously affect cancer cells in vitro.
Method: Microcrystalline cellulose is oxidized and cellulose dialdehyde is
synthesized. The synthesized cellulose dialdehyde in combination with
oleylamine provides a dual-functional cellulose-based nanoparticle with
aldehyde and amine functional groups. The poly-L-lysine polymer forms a
polyplex through electrostatic bonding with miR-34a. Dual-functional cellulose
nanoparticles simultaneously load miR-34a and 3MA through self-assembly. The
physicochemical properties of this nanoparticle loaded with therapeutic agents
were evaluated. In addition, MTT, cell uptake, apoptosis, cell cycle, Western blot
and Real-time PCR tests were performed to investigate the effect of this
nanoparticle on the HepG2 cell line.
Findings: In the present study, a modified dialdehyde cellulose (MDAC)
nanocarrier that responds to lysosomal pH was designed to simultaneously load
polyplexes of hsa-miR-34a and 3MA and evaluate its antitumor effect against
HCC cells. The polyplexes containing hsa-miR-34a and poly L-lysine (PLL) with
an optimal N/P ratio of 1:20 exhibited a zeta potential of +9.28. These polycations
significantly modulated the surface charge of 3MA MDAC for optimal cell
membrane transport and significantly increased their stability. The PLLmiR34a/3MA MDAC nanoparticles had a loading efficiency of about 99.7% for
miR-34a and 35% for 3MA. In accordance with pH dependence, PLLmiR34a/3MA MDAC polyplex nanoparticles inhibited the expression ofautophagy genes (p<0.05), prevented the formation of autophagosomal vacuoles
and were highly effective in reducing cell survival, anti-migratory effects (>100%
scratch) and scratch blockage (early + late apoptosis = 67.15%) in HepG2 cells.
Our cellulose-based nanocarrier may show the potential to enhance the
combination therapies for future clinical translation in therapeutic efficacy of
HCC.
Conclusion: This is the first study in which 3MA and miR-34a were coloaded onto dual-drug cellulose nanoparticles. The cellulose-based nanocarrier
enhanced the anticancer efficacy of the loaded therapeutic agents compared to
the free state.
Keywords: Hepatocellular carcinoma, cellulose-based nanocarrier, 3MA,
miR-34a, autophagy, apoptosis | en_US |
