Mesoporous silica nanoparticles (MSNs) are known as carriers with high loading capacity and large functionalizable surface area for target-directed delivery. In this study, a series of docetaxel-loaded folic acid- or methionine-functionalized mesoporous silica nanoparticles (DTX/MSN-FA or DTX/MSN-Met) with large pores and amine groups at inner pore surface properties were prepared. The results showed that the MSNs were successfully synthesized, having good pay load and pH-sensitive drug release kinetics. The cellular investigation on MCF-7 cells showed better performance of cytotoxicity and cell apoptosis and an increase in cellular uptake of targeted nanoparticles. In vivo fluorescent imaging on healthy BALB/c mice proved that bare MSN-NH2 are mostly accumulated in the liver but MSN-FA or MSN-Met are more concentrated in the kidney. Importantly, ex vivo fluorescent images of tumor-induced BALB/c mice organs revealed the ability of MSN-FA to reach the tumor tissues. In conclusion, DTX/MSNs exhibited a good anticancer activity and enhanced the possibility of targeted drug delivery for breast cancer.
Although siRNA is a promising technology for cancer gene therapy, effective cytoplasmic delivery has remained a significant challenge. In this paper, a potent siRNA transfer system with active targeting moieties toward cancer cells and a high loading capacity is introduced to inhibit drug resistance. Mesoporous silica nanoparticles are of great potential for developing targeted gene delivery. Amino-modified MSNs (NH2-MSNs) were synthesized using a modified sol–gel method and characterized by FTIR, BET, TEM, SEM, X-ray diffraction, DLS, and 1H-NMR. MDR1-siRNA was loaded within NH2-MSNs, and the resulting negative surface was capped by functionalized chitosan as a protective layer. Targeting moieties such as TAT and folate were anchored to chitosan via PEG-spacers. The loading capacity of siRNA and the protective effect of chitosan for siRNA were determined by gel retardation assay. MTT assay, flow cytometry, real-time PCR, and western blot were performed to study the cytotoxicity, cellular uptake assay, targeting evaluation, and MDR1 knockdown efficiency. The synthesized NH2-MSNs had a particle size of ≈ 100 nm and pore size of ≈ 5 nm. siRNA was loaded into NH2-MSNs with a high loading capacity of 20% w/w. Chitosan coating on the surface of siRNA-NH2-MSNs significantly improved the siRNA protection against enzyme activity compared to naked siRNA-NH2-MSNs. MSNs and modified MSNs did not exhibit significant cytotoxicity at therapeutic concentrations in the EPG85.257-RDB and HeLa-RDB lines. The folate-conjugated nanoparticles showed a cellular uptake of around two times higher in folate receptor-rich HeLa-RDB than EPG85.257-RDB cells. The chitosan-coated siRNA-NH2-MSNs produced decreased MDR1 transcript and protein levels in HeLa-RDB by 0.20 and 0.48-fold, respectively. The results demonstrated that functionalized chitosan-coated siRNA-MSNs could be a promising carrier for targeted cancer therapy. Folate-targeted nanoparticles were specifically harvested by folate receptor-rich HeLa-RDB and produced a chemosensitized phenotype of the multidrug-resistant cancer cells.
Gene therapy using biocompatible cationic liposomes is amongst promising approaches that decreases death from cancers. Here an invasive multidrug resistant cell model has been developed by lentiviral transfection. In parallel phospholipids have been covalently conjugated to TAT, MMP2, and Herceptin. The functional lipids have been mixed to generate intelligent liposome harboring small interfering RNA (siRNA) with high efficiency. The final liposomal complex was uniformly monodisperse and particle dimension and zeta-potential were respectively around 200 nm and −42.21 mV.Minimal cytotoxic effects have been reported for nanocarriers due to good biocompatibility of the selected phospholipids. Flourescence-activated cell sorter (FACS) analyses have been represented that surface trastuzumab and TAT specifically promote cellular uptake of liposomes in the malignant tumor cells. Assessment of MDR1 transcript and protein expression has been exhibited maximum significant downregulation around of 128-fold and 50-fold, respectively after 48 hr of liposome exposure. As it has been concluded, targeted liposomes may become a potential tool in gene delivery for improving chemotherapeutic efficiency in cancer treatment.
Resistance to temozolomide (TMZ) is the main cause of death in glioblastoma multiforme (GBM). The use of nanocarriers for drug delivery applications is one of the known approaches to overcome drug resistance. This study aimed to investigate the possible effect of selenium–chitosan nanoparticles loaded with TMZ on the efficacy of TMZ on the expression of MGMT, E2F6, and RELA genes and the rate of apoptosis in the C6 cell line. Selenium nanoparticles (SNPs) were loaded with TMZ and then they were coated by Eudragit® RS100 (Eud) and chitosan (CS) to prepare Se@TMZ/Eud-Cs. Physicochemical properties were determined by scanning electron microscope (SEM), energy-dispersive X-ray spectroscopy (EDAX), thermal gravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FTIR), and dynamic light scattering (DLS) methods. Se@TMZ/Eud-Cs was evaluated for loading and release of TMZ by spectrophotometric method. Subsequently, SNPs loaded with curcumin (as a fluorophore) were analyzed for in vitro uptake by C6 cells. Cytotoxicity and apoptosis assay were measured by MTT assay and Annexin-PI methods. Finally, real-time PCR was utilized to determine the expression of MGMT, E2F6, and RELA genes. Se@TMZ/Eud-Cs was prepared with an average size of 200 nm as confirmed by the DLS and microscopical methods. Se@TMZ/Eud-Cs presented 82.77 ± 5.30 loading efficiency with slow and pH-sensitive release kinetics. SNPs loaded with curcumin showed a better uptake performance by C6 cells compared with free curcumin (p-value < 0.01). Coated nanoparticles loaded with TMZ showed higher cytotoxicity, apoptosis (p-value < 0.0001), and down-regulation of MGMT, E2F6, and RELA and lower IC50 value (p-value < 0.0001) than free TMZ and control (p-value < 0.0001) groups. Using Cs as a targeting agent in Se@TMZ/Eud-Cs system improved the possibility for targeted drug delivery to C6 cells. This drug delivery system enhanced the apoptosis rate and decreased the expression of genes related to TMZ resistance. In conclusion, Se@TMZ/Eud-Cs may be an option for the enhancement of TMZ efficiency in GBM treatment.
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