Inhibiting notch activity in liver cancer stem cells by functionalized gold nanoparticles with gamma-secretase inhibitor dapt and vitamin c
,1 Mostafa shourian
1. University of Guilan
2. University of Guilan
Liver cancer is one of the most common malignancies and the second leading cause of cancer-related death worldwide. hepatocellular carcinoma (hcc) is the most common type of primary liver cancer cases and it is characterized by a high recurrence rate and heterogeneity. these pathological properties may ﬂow from cancer stem cells (cscs), which are capable of self-renewal and differentiation responsible for tumor progression, metastasis, and chemotherapy-resistance. notch signaling has been implicated to regulate the csc population, where it has been shown to be critical for maintenance and self-renewal of cscs. notch is linked to aggressive metastatic growth and therapy resistance and one method of effectively blocking notch activity is preventing its cleavage at the cell surface with γ-secretase inhibitors. another novel therapeutic strategy for hcc treatment is vitamin c (vc). vc kills cancer cells and preferentially kills cscs via svct-2. the nanomaterials are used as beneficial tools for targeting different types of therapeutic agents, including carbon nanotubes, quantum dots, liposomes, micelles, polymeric, graphene, gold nanoparticles (au nps), ferroferric oxide nanoparticles and so on. recently, among the various types of nanomaterials, the biomedical consumption of metallic nanoparticles, especially gold nanoparticles, has attracted a lot of attention because of their unique properties. these days, gold nanoparticles due to their nontoxicity, biocompatibility, ease of synthesis and surface functionalization have been chosen for different kinds of biomedical applications such as molecular imaging, drug carriers, biosensing, killers of cancer cells by hyperthermia treatment and etc. the conjugation of gold nps-drug in comparison to the free drug was shown to increase drug availability in circulation. on the other hand, most of the studies dedicated to cancer treatment have shown that angiogenesis plays an important role in growth and metastasis of solid tumors.
Utilizing these csc features, au nps were synthesized according to previous method with little modifications by addition of tri-sodium citrate solution to aqueous solution of haucl4 for reduction of chloroauric acid. we made the gold nanoparticles (gnps) suspension using a reference method, by adding 2 ml of trisodium citrate 1% to 50 ml of aqueous solution of 1% haucl4. following that, their surface was self assembled by cystamine. after that, we functionalized au nanoparticles covalently, by using the activation of carboxyl groups of dapt and vc for binding to amine group of cystamine, mes buffer containing edc/nhs were used.
We functionalized au nanoparticles, carrying gamma-secretase inhibitor, dapt, with vc to efficiently deliver notch signaling inhibitors to cscs via svct-2. the vc and dapt were co-immobilized on surface of gold nanoparticle. uv-vis spectroscopy as the most basic and appropriate method was used to evaluate the size of gnps and gnps-dapt/vc in suspension. the diameter of the au nps and gnps-dapt/vc were figured out by dls approximately under 20 nm.
We aimed to enhance particle uptake in cscs by utilizing the machinery for cellular import of vc. our data reveal that speciﬁc csc characteristics can be utilized in nanoparticle design to improve csc targeted drug delivery and therapy.
Gamma-secretase inhibitor, dapt, gold nanoparticles, vitamin c, liver cancer