Targeted Gene Silencing BRAF Synergized Photothermal Effect Inhibits Hepatoma Cell Growth Using New GAL-GNR-siBRAF Nanosystem (original) (raw)
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Nanomedicine : nanotechnology, biology, and medicine, 2018
Melanoma is significantly associated with mutant BRAF gene, a suitable target for siRNA-based anti-melanoma therapy. However, a tumor-specific delivery system is a major hurdle for clinical applications. Here, we developed a novel nano-carrier, FA-GNR-siBRAF for safe topical application, which consists of folic acid (FA) as the tumor-targeting moiety, golden nanorods (GNR) providing photothermal capability to kill tumor cells under laser irradiation, and siRNA specifically silencing BRAF (siBRAF). The in vitro and in vivo results revealed that FA-GNR-siBRAF displayed high transfection rates, and subsequently induced remarkable gene knockdown of BRAF, resulting in suppression of melanoma growth due to the interruption of the MEK/ERK pathway. Combinatorial photothermal effects and BRAF knockdown by FA-GNR-siBRAF effectively killed tumor cells through apoptosis, with enhanced efficiency than individual treatments. Therefore, the FA-GNR-siBRAF simultaneously induced BRAF gene silencing ...
Theranostics, 2015
In this work, we report the engineering of polyelectrolyte polymers coated Gold nanorods (AuNRs)-based nanocarriers that are capable of co-delivering small interfering RNA (siRNA) and an anticancer drug doxorubicin (DOX) to Panc-1 cancer cells for combination of both chemo-and siRNA-mediated mutant K-Ras gene silencing therapy. Superior anticancer efficacy was observed through synergistic combination of promoted siRNA and DOX release upon irradiating the nanoplex formulation with 665 nm light. Our antitumor study shows that the synergistic effect of AuNRs nanoplex formulation with 665 nm light treatment is able to inhibit the in vivo tumor volume growth rate by 90%. The antitumor effect is contributed from the inactivation of K-Ras gene and thereby causing a profound synthesis (S) phase arrest in treated Panc-1 cells. Our study shows that the percentage of Panc-1 cells treated by nanoplex formulation with S phase is determined to be 35% and it is 17% much higher than that of Panc-1 cells without any treatments. The developed nanotherapy formulation here, that combines chemotherapy, RNA silencing and NIR window light-mediated therapy, will be seen to be the next natural step to be taken in the clinical research for improving the therapeutic outcomes of the pancreatic adenocarcinoma treatment.
Modified gold nanoparticles for intracellular delivery of anti-liver cancer siRNA.pdf
To overcome the rapid enzymatic degradation and low transfection efficiency of siRNA, the delivery carriers for siRNA is a therapeutic demand to increase its stability. Gold nanoparticles (AuNPs) modified by branched polyethyleneimine (bPEI) were developed as an efficient and safe intracellular delivery carriers for siRNA. The current study implied that siRNA designed against an oncogene c-Myc could be delivered by a modified AuNPs complex without significant cytotoxicity. The comparative semiquantitative and quantitative real time PCR were used to measure the c-Myc gene expression after transfection with naked siRNA and siRNA/bPEI/AuNPs, but AuNPs interfered with PCR. However, the c-Myc protein translation was successfully detected in the transfected HuH7 cells with naked siRNA and siRNA/bPEI/AuNPs and it was found to be inhibited by siRNA/bPEI/AuNPs more than naked siRNA. The results validate the successful silencing of c-Myc gene. Accordingly, it may confirm the promising and effective delivery of siRNA by bPEI/AuNPs. The complex enhances the cellular uptake of siRNA without significant cytotoxicity and confirms that bPEI modified AuNPs could be used as a good candidate for safe cellular delivery of siRNA.
2014
Biomarker-specific photothermal nanoparticles that can efficiently sense markers that are overexpressed in distinguished adenocarcinomas have attracted much interest in an aspect of efficacy increase of cancer treatment. We demonstrated a promising prospect of a smart photothermal therapy agent employing anti-epidermal growth factor receptor aptamer (Apt EGFR )-conjugated polyethylene glycol (PEG) layted gold nanorods (Apt EGFR -PGNRs). The cetyltrimethylammonium bromide bilayer on GNRs was replaced with heterobifunctional PEG (COOH-PEG-SH) not only to serve as a biocompatible stabilizer and but also to conjugate Apt EGFR . Subsequently, to direct photothermal therapy agent toward epithelial cancer cells, the carboxylated PEGylated GNRs (PGNRs) were further functionalized with Apt EGFR using carbodiimide chemistry. Then, to assess the potential as biomarker-specific photothermal therapy agent of synthesized Apt EGFR -PGNRs, the optical properties, biocompatibility, colloidal stability, binding affinity, and epicellial cancer cell killing efficacy in vitro/in vivo under near-infrared laser irradiation were investigated. As a result, Apt EGFR -PGNRs exhibit excellent tumor targeting ability and feasibility of effective photothermal ablation cancer therapy.
NIR triggered glycosylated gold nanoshell as a photothermal agent on melanoma cancer cells
Artificial Cells, Nanomedicine, and Biotechnology
Nowadays, gold nanoshells are used in targeted nano photothermal cancer therapy. This study surveyed the application of gold nanoshell (GNs) to thermal ablative therapy for melanoma cancer cells and it takes advantage of the near infrared absorption of gold nanoshells. The synthesis and characterization of glycosylated gold nanoshells (GGNs) were done. The cytotoxicity and photothermal effects of GNs on melanoma cells were evaluated using MTT assay and flow cytometry. The characterization data showed that GGNs are spherical, with a hydrodynamic size of 46.7 nm. Results suggest that the cellular uptake of GGNs was about 78%. Viability assays showed no significant toxicity at low concentrations of GNs. The higher heating rate and toxicity of cancer cells were obtained for the cells exposed to 808 nm NIR laser after incubation with GGNs rather than the GNs. The viability of these cells has dramatically decreased by 29%. Furthermore, 61% more cell lethality was achieved for A375 cells using combined photothermal therapy and treatment with GGNs in comparison to NIR radiation alone. In conclusion, our findings suggest that the synthesized gold/silica core-shell nanoparticles conjugated with glucosamine have high potentials to be considered as an efficient metal-nanoshell in the process of targeted cancer photothermal therapy.
Cancer Research, 2010
Nuclear factor-κB (NF-κB) transcription factor is a critical regulator of the expression of genes involved in tumor formation and progression. Successful RNA interference (RNAi) therapeutics targeting NF-κB is challenged by siRNA delivery systems, which can render targeted in vivo delivery, efficient endo-lysosomal escape and dynamic control over activation of RNAi. Here, we report near-infrared light-inducible NF-κB down-regulation through folate receptor-targeted hollow gold nanospheres carrying siRNA recognizing NF-κB p65 subunit. Using micro-positron emission tomography/computed tomography imaging, the targeted nanoconstructs exhibited significantly higher tumor uptake in nude mice-bearing HeLa cervical cancer xenografts than nontargeted nanoparticles following intravenous administration. Mediated by hollow gold nanospheres, controllable cytoplasmic delivery of siRNA was obtained upon near-infrared light irradiation through photothermal effect. Efficient down-regulation of NF-κB p65 was achieved only in tumors irradiated with near-infrared light, but not in non-irradiated tumors grown in the same mice. Liver, spleen, kidney, and lung were not affected by the treatments, in spite of significant uptake of the siRNA nanoparticles in these organs. We term this mode of action "photothermal transfection". Combined treatments with p65 siRNA photothermal transfection and irinotecan caused substantially enhanced tumor apoptosis and significant tumor growth delay compared with other treatment regimens. Therefore, photothermal transfection of NF-κB p65 siRNA could effectively sensitize the tumor to chemotherapeutic agents. Because NIR light can penetrate skin and be delivered with high spatiotemporal control, therapeutic RNAi may benefit from this novel transfection strategy while avoiding unwanted side effect.
Journal of Biomedical Nanotechnology, 2016
Photothermal therapy has great significant as a new technology for cancer treatment without side effects. Especially with near-infrared laser as the driving force, which has shown a promising prospect in cancer treatment. However, its application is based on the development of near-infrared laser response of photothermal conversion nanomaterials. Nanogold materials have been studied for a long time as light sensitive materials. The main reason is the surface of the plasmon resonance effect can be adjusted by surface, size and structure, which could make them have excellent performance while absorbing the specific optical wavelength and completing energy convertion. We used the biocompatible gold nano-rods (GNRs) as probes for cancer targeting in order to introduce a progressive synthesis approach in fabricating water-dispersible gold nanorods. These nanorods were prepared by replacing cetyltrimethylammonium bromide with a mixture of 15-polypeptide(15P) molecules. The nano size was estimated about 70-80 nm by electron microscope. The result of dynamic light scattering showed that the cores of the gold nanorods were protected from the outside environment by the 15-polypeptide. Photothermal treatment indicated that 15P-GNRs could stain tumor growth and devote the pivotal steps in promoting cancer cell death with near-infrared laser irradiation. More importantly, these results proved that 15P-GNRs has good bio-compatiblility and can be considered as photothermal conversion material for targeting the ovarian tumor.
ACS Applied Materials & Interfaces, 2016
Experimental section Materials: Iron(III) chloride hexahydrate (FeCl3.6H2O), gold (III) chloride solution (HAuCl4), tetramethylammonium hydroxide (TMAOH), oleylamine, fluorescein isothiocyanate isomer I (FITC) and cetyltrimethylammonium bromide (CTAB) were purchased from Sigma Aldrich Co., USA. Sodium oleate, oleic acid, sodium hydroxide (NaOH), silver nitrate (AgNO3), sodium borohydride and acetone were procured from Merck, India. Ascorbic acid and bovine serum albumin (BSA) were obtained from Sisco Research Laboratories Pvt. Ltd., India. Doxorubicin hydrochloride (Dox) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) were from Parental Drugs India Ltd. and Himedia, India, respectively. All chemicals were used without further purification. Milli-Q grade water (>18 MΩ cm, Millipore) was used in all the experiments. Preparation of gold nanorods (Au NRs): Au NRs were prepared by following the method developed by Sau et al. 1 To prepare gold seed particles, 7.5 mL of CTAB (0.1 M) solution and
Proceedings of the National Academy of Sciences of the United States of America, 2017
Gold nanorods (AuNRs)-assisted plasmonic photothermal therapy (AuNRs-PPTT) is a promising strategy for combating cancer in which AuNRs absorb near-infrared light and convert it into heat, causing cell death mainly by apoptosis and/or necrosis. Developing a valid PPTT that induces cancer cell apoptosis and avoids necrosis in vivo and exploring its molecular mechanism of action is of great importance. Furthermore, assessment of the long-term fate of the AuNRs after treatment is critical for clinical use. We first optimized the size, surface modification [rifampicin (RF) conjugation], and concentration (2.5 nM) of AuNRs and the PPTT laser power (2 W/cm(2)) to achieve maximal induction of apoptosis. Second, we studied the potential mechanism of action of AuNRs-PPTT using quantitative proteomic analysis in mouse tumor tissues. Several death pathways were identified, mainly involving apoptosis and cell death by releasing neutrophil extracellular traps (NETs) (NETosis), which were more obv...
Small (Weinheim an der Bergstrasse, Germany), 2015
Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide. Small interfering RNA (siRNA) holds promise as a new class of therapeutics for HCC, as it can achieve sequence-specific gene knockdown with low cytotoxicity. However, the main challenge in the clinical application of siRNA lies in the lack of effective delivery approaches that need to be highly specific and thus incur low or no systemic toxicity. Here, a nonviral nanoparticle-based gene carrier is presented that can specifically deliver siRNA to HCC. The nanovector (NP-siRNA-GPC3 Ab) is made of an iron oxide core coated with chitosan-polyethylene glycol (PEG) grafted polyethyleneimine copolymer, which is further functionalized with siRNA and conjugated with a monoclonal antibody (Ab) against human glypican-3 (GPC3) receptor highly expressed in HCC. A rat RH7777 HCC cell line that coexpresses human GPC3 and firefly luciferase (Luc) is established to evaluate the nanovector. The nanoparticle-mediated delivery of...