Title:Improving Tamoxifen Performance in Inducing Apoptosis and Hepatoprotection by
Loading on a Dual Nanomagnetic Targeting System
Volume: 24
Issue: 13
Author(s): Yanfang Zhao, Wanbao Ding, Peixian Zhang, Lei Deng, Yi Long, Jiuqin Lu*, Fereshteh Shiri and Mostafa Heidari Majd
Affiliation:
- Key Laboratory of Tumor Immunological Prevention and Treatment, Department of Oncology, Yan’An Affiliated Hospital of Kunming
Medical University, Kunming, Yunnan, 650118, China
Keywords:
Magnetic nanoparticles, drug delivery, flow cytometry, real time PCR, hyaluronic acid, Bcl-2 family proteins, hepatotoxicity.
Abstract:
Background: Although tamoxifen (TMX) belongs to selective estrogen receptor modulators (SERMs)
and selectively binds to estrogen receptors, it affects other estrogen-producing tissues due to passive diffusion and
non-differentiation of normal and cancerous cells and leads to side effects.
Methods: The problems expressed about tamoxifen (TMX) encouraged us to design a new drug delivery system
based on magnetic nanoparticles (MNPs) to simultaneously target two receptors on cancer cells through folic acid
(FA) and hyaluronic acid (HA) groups. The mediator of binding of two targeting agents to MNPs is a polymer
linker, including dopamine, polyethylene glycol, and terminal amine (DPN).
Results: Zeta potential, dynamic light scattering (DLS), and Field emission scanning electron microscopy
(FESEM) methods confirmed that MNPs-DPN-HA-FA has a suitable size of ~105 nm and a surface charge of -41
mV, and therefore, it can be a suitable option for carrying TMX and increasing its solubility. The cytotoxic test
showed that the highest concentration of MNPs-DPN-HA-FA-TMX decreased cell viability to about 11% after 72
h of exposure compared to the control. While the protective effect of modified MNPs on normal cells was evident,
unlike tamoxifen, the survival rate of liver cells, even after 180 min of treatment, was not significantly different
from the control group. The protective effect of MNPs was also confirmed by examining the amount of
malondialdehyde, and no significant difference was observed in the amount of lipid peroxidation caused by modified
MNPs compared to the control. Flow cytometry proved that TMX loaded onto modified MNPs can induce apoptosis
by targeting the overexpressed receptors on cancer cells. Real-time PCR showed that the modified MNPs activated
the intrinsic and extrinsic mitochondrial pathways of apoptosis, so the Bak1/Bclx ratio for MNPs-DPN-HAFA-
TMX and free TMX was 70.82 and 0.38, respectively. Also, the expression of the caspase-3 gene increased 430
times compared to the control. On the other hand, only TNF gene expression, which is responsible for metastasis in
some tumors, was decreased by both free TMX and MNPs-DPN-HA-FA-TMX. Finally, molecular docking proved
that MNPs-DPN-HA-FA-TMX could provide a very stable interaction with both CD44 and folate receptors, induce
apoptosis in cancer cells, and reduce hepatotoxicity.
Conclusion: All the results showed that MNPs-DPN-HA-FA-TMX can show good affinity to cancer cells using
targeting agents and induce apoptosis in metastatic breast ductal carcinoma T-47D cell lines. Also, the protective
effects of MNPs on hepatocytes are quite evident, and they can reduce the side effects of TMX.
