Functionalized Gold Nanorods Research Articles

Gold Nanorod Enhanced Photoacoustic Microscopy and Optical Coherence Tomography of Choroidal Neovascularization.

Visualization and evaluation of choroidal neovascularization (CNV) are major challenges to improve treatment outcomes for patients with age-related macular degeneration (AMD). Limitations of current imaging techniques include the limited penetration depth, spatial resolution, and sensitivity and difficulty visualizing CNV from the healthy microvasculature. In this study, a custom-built multimodal photoacoustic microscopy (PAM) and optical coherence tomography (OCT) system was developed to distinguish the margin of CNV in living rabbits with the assistance of functionalized gold nanorods conjugating with RGD ligands (GNR-RGD). Intravenous administration of GNR-RGD into rabbits in a CNV model resulted in signal enhancements of 27.2-fold in PAM and 171.4% in OCT. This molecular imaging technique of contrast-enhanced PAM and OCT is a promising tool for the precise imaging of CNV as well as the evaluation of the pathophysiology in vivo without destruction of tissue.

Multifunctional Gold Nanorod for Therapeutic Applications and Pharmaceutical Delivery Considering Cellular Metabolic Responses, Oxidative Stress and Cellular Longevity.

Multifunctional gold nanorods (GNR) have drawn growing interest in biomedical fields because of their excellent biocompatibility, ease of alteration, and special optical properties. The great advantage of using GNR in medicine is their application to Photothermal therapy (PPTT), which is possible thanks to their ability to turn luminous energy into heat to cause cellular hyperthermia. For this purpose, the relevant articles between 1988 and 2020 were searched in databases such as John Wiley, Free paper, Scopus, Science Direct, and Springer to obtain the latest findings on multifunctional gold nanorods for therapeutic applications and pharmaceutical delivery. In this article, we review recent progress in diagnostic and therapeutic applications of multifunctional GNR, highlighting new information about their toxicity to various cellular categories, oxidative stress, cellular longevity, and their metabolic effects, such as the effect on the energy cycles and genetic structures. The methods for the synthesis and functionalization of GNR were surveyed. This review includes new information about GNR toxicity to various cellular categories and their metabolic effects.

A Nucleic Acid/Gold Nanorod-Based Nanoplatform for Targeted Gene Editing and Combined Tumor Therapy.

The CRISPR/Cas9 gene-editing system has become a promising strategy for tumor therapy with its powerful oncogene-editing ability. However, the efficient delivery of sgRNA/Cas9 complex into target tumor cells remains a challenge. Herein, we report a facile strategy for the construction of an sgRNA/Cas9 complex co-assembled nanoplatform for targeted gene editing and combined tumor therapy. In our design, the TAT peptide and thiolated DNA linker functionalized gold nanorod can efficiently load the sgRNA/Cas9 complex through the hybridization between the 3' overhang of sgRNA and the DNA linker. Due to the integration of an active cell targeting group (aptamer) and nuclear targeting peptide (TAT), the multifunctional nanoplatform can elicit the targeted cellular internalization and efficient nuclear targeting transportation to realize endogenous RNase H activated gene editing of the tumor-associated gene polo-like kinase 1 (PLK1). With mild photothermal treatment, this sgRNA/Cas9 complex loaded nanoplatform achieved efficient inhibition of tumor cell proliferation. This multifunctional nanocarrier provides a new strategy for the development of combined tumor therapy.

Aptamer and RVG functionalized gold nanorods for targeted photothermal therapy of neurotropic virus infection in the mouse brain

The infection of the neurotropic virus damages the central nervous system (CNS) and often leads to humans' fatal symptoms. Rabies is a lethal disease caused by a typical neurotropic virus, rabies virus (RABV). To date, there is no effective clinical therapy for rabies. In this report, an aptamer conjugated RVG-Apt-PEG-Silica gold nanorods (AuNR)-based photothermal therapy (PTT) was developed and evaluated in a mouse model. The DNA aptamer was conjugated on the nanoparticle to provide specificity for targeting RABV glycoprotein in cells and mouse brains. A 29-aa rabies virus glycopeptide (RVG) was conjugated on the nanoparticle to enhance CNS delivery. The virions were inactivated in cell supernatant, and an approximately 100-fold decrease of viral load was observed in cells 5 min post-PTT. This AuNR did not cause distinct apoptosis, inflammation, or pathological lesion in the mouse brains post PTT. At 3 day post-infection, significantly enhanced survival ratio (60%) was observed in mice received PTT compared with the mice without PTT. In the PTT group, both the viral RNA level and the distribution of RABV in mouse brains were significantly decreased. Collectively, aptamer conjugated RVG-Apt-PEG-Silica AuNR-based PTT could be considered as a promising strategy for clinical treatment with neurotropic virus infection.

Study of the interaction of folic acid-modified gold nanorods and fibrinogen through microfluidics: implications for protein adsorption, incorporation and viability of cancer cells.

Gold nanoparticles (GNPs) are an attractive nanomaterial for potential applications in therapy and diagnostics due to their capability to direct toward specific sites in the organism. However, when exposed to plasma, GNPs can interact with different biomolecules that form a dynamic nano-bio interface called a "protein corona" (PC). Remarkably, the PC could affect multiple biological processes, such as cell targeting and uptake, cytotoxicity, and nanoparticle (NP) clearance. The interaction of nanomaterials with plasmatic proteins has been widely studied under bulk conditions, however, under dynamic conditions, it has just recently been explored. Thus, to mimic a dynamic natural environment found in arteries and veins, microfluidic devices were used. In this work, gold nanorods (GNRs) were synthesized and conjugated with polyethylene glycol (PEG) to reduce their interaction with plasma proteins and increase their biocompatibility. Then, GNRs were functionalized with folic acid, a targeting ligand typically used to recognize tumor cells. The resulting nanosystem was exposed to fibrinogen (FB) to study the development and biological impact of PC formation through two strategies: bulk and laminar flow conditions. The obtained nanosystems were characterized by absorption spectrophotometry, DLS, laser Doppler microelectrophoresis, neutron activation analysis, circular dichroism spectroscopy and TEM. Finally, cell viability and cellular uptake assays were performed to study the influence of the PC on the cell viability and delivery of nanosystems.

Surface functionalized gold nanorods for plasmonic photothermal therapy

Gold nanorods (GNR) are considered as potential candidates for varied biological applications. They are synthesized using the cationic surfactant layers such as cetyltrimethylammonium bromide (CTAB), which create the limitation towards biocompatibility quotient. To overcome these issues, CTAB-GNR were functionalized by ligand exchange method in which first step is the pegylation followed by conjugation with RGD (arginine-glycine-aspartic acid) to the pegylated entity. RGD conjugation was done to target the overexpressed αvβ3 integrin present in cancerous cells thereby enhancing the therapeutic response of the developed system for photothermal therapy. GNR of requisite size were synthesized through two step seed mediated growth process and then functionalized with RGD through carbodiimide coupling reaction to get a biocompatible system. The RGD functionalized GNR were characterized by UV–VIS spectroscopy, Fourier transform infrared spectroscopy (FT-IR). In addition, the size and shape of GNR were confirmed using transmission electron microscopy (TEM). The photothermal studies were performed using 808 nm laser diode. Cytotoxicity studies were conducted on MDA-MB-231 cancer cells using MTT Assay.

Surface acoustic wave (SAW) sensor for volatile organic compounds (VOCs) detection with calix[4]arene functionalized Gold nanorods (AuNRs) and silver nanocubes (AgNCs)

Abstract The detection of chemicals in gas-phase has been employed in a wide variety of applications, including indoor air quality and environmental monitoring, chemical and biochemical processing, and medical diagnostics such as lung cancer screening. In this study, gold nanorod (AuNR) and silver nanocube (AgNC) molecules were functionalized with thiol (S- terminal) containing Calix[4]arene and were investigated for their molecular recognition properties on surface acoustic wave (SAW) transducer device surfaces. These novel sensing materials on transducer SAW device were investigated for the detection of polar (acetone, ethanol, chloroform, and humidity) and nonpolar (n-hexane, toluene, isoprene) volatile organic compounds (VOCs), among which are key markers for disease diagnosis, such as toluene present in exhaled breath of lung cancer patients. Sensor responses were discussed under various concentration levels in terms of selectivity, sensitivity, limit of detection, and response time. After AuNR and AgNC modification with Calix[4]arene, sensitivity of sensors has reached up to six to eight-fold higher than the individual responses, with a selectivity towards chloroform and toluene, respectively.

Layer-by-layer Functionalization of Gold Nanorods by Polyelectrolytes to Control Surface Spacer and Precisely Tune the Surface Plasmon Resonance Position

We present a layer-by-layer functionalization of gold nanorods (GNRs) by polyelectrolytes in order to control precisely the spacer surrounding the metallic nanoparticles but also to modulate its plasmonic properties. Alternate functionalization with negatively and positively charged polyelectrolytes ensures a 2 nm step control of the spacer from 0 nm up to 10 nm, depending on the number of layers. Such process changes the local refractive index and thus induces a red shift of the surface plasmon resonance. Both solution and solid samples were studied.

Hairpin Oligonucleotide Can Functionalize Gold Nanorods for in Vivo Application Delivering Cytotoxic Nucleotides and Curcumin: A Comprehensive Study in Combination with Near-Infrared Laser.

We prepared a multimodality nanocomplex by functionalizing gold nanorods (GNRs) with a cytotoxic nucleoside, 5-fluoro-2′-deoxyuridine (FdU) containing a DNA hairpin, along with complexation of pleiotropic molecule curcumin. Conjugates were investigated for anti-tumor activity using an Ehrlich carcinoma model in combination with 808 nm laser irradiation. We demonstrated that hairpin-functionalized GNRs are suitable for intravenous administration, including delivery of cytotoxic nucleotides and curcumin. Curcumin binding with FdU-hairpin-functionalized GNRs displayed improved anti-tumor activity in part by inducing a lymphocyte-mediated immune response. The complex showed notable photothermal activity in vitro; however, 808 nm laser irradiation of the tumor following treatment with the complex did not increase the anti-tumor effect significantly. Biodistribution studies depicted that the nanoconjugates localized primarily in the sinusoidal structures of the liver and spleen with minimal tumor accumulation. Curcumin complexation alleviated the reduction in the RBC count that was observed for the conjugate without curcumin, especially in combination with laser irradiation. Localization of FdU-hairpin-GNR conjugates in the liver and spleen evoked an inflammatory response, which was mitigated by curcumin complexation. However, no functional abnormality was found in the liver in any case. Curcumin binding also notably decreased nanoconjugate accumulation in lungs and significantly reduced inflammation. Biodistribution studies were consistent with previous reports, suggesting that optimization of the GNR size and surface coating is required for more efficient tumor localization via the enhanced permeability and retention (EPR) effect. Our studies demonstrate that DNA/RNA hairpins are suitable for GNR surface functionalization and enable delivery of cytotoxic nucleotides as well as curcumin in vivo with potential for synergistic anti-cancer therapy.

Hyaluronic acid-coated gold nanorods enhancing BMP-2 peptide delivery for chondrogenesis

Bone morphogenic protein-2 (BMP-2) knuckle epitope peptide has been recently discovered and known to activate chondrogenesis. However, the applications of this soluble peptide remain very limited due to rapid diffusion resulting in poor cellular uptake into target cells. We herein designed nanoparticles made from hyaluronic acid functionalized gold nanorods (GNRs) to conjugate with thiolated BMP-2 knuckle epitope peptide via a two-step reaction. Hyaluronic acid was modified to have thiol functional groups to replace the cetyl trimethylammonium bromide ligands on the surface of GNRs. The thiolated peptides were subsequently reacted with hyaluronic acid on the surface on GNRs via a maleimide-hydrazide crosslinker. The conjugation was confirmed by the change of surface charge of GNRs and the plasmon shift. A colorimetric peptide assay suggested more than 69% of the thiolated peptides were conjugated with the hyaluronic acid coated gold nanorods. Moreover, in vitro cell viability showed that BMP-2 conjugated hyaluronic acid functionalized gold nanorods (B2HGR) were cytocompatible and did not cause cytotoxicity to fibroblast cells. The B2HGRs also significantly promote cellular uptake of the BMP-2 peptides in both human mesenchymal stem cells and porcine chondrocytes due to multivalent ligand binding to the BMP receptors on the cell surface resulting in receptor-mediated endocytosis. The enhanced cellular uptake was clearly observed under a confocal microscope resulting in the significant activation of type II collagen gene expression and glucosaminoglycan secretion in those cells. Furthermore, our delivery system is a proof-of-concept of using scaffolds in combination with nanodelivery platform to enhance cartilaginous repair. The peptide loading capacity and the release is not limited by the scaffolds. Therefore, our delivery platform has potential applications for cartilage regeneration in a preclinical and clinical setting in the future.

Carboxyl functionalized gold nanorods for sensitive visual detection of biomolecules

Antibody-modified gold nanomaterials are central to many novel biosensing technologies for example the lateral flow assays technology. The combination of the specificity, provided by antibody–antigen interactions, and the unique optical properties of nanomaterials provide excellent properties for biosensors. Here, we present the use of gold nanorods (GNR) with the localized Surface Plasmon Resonance (LSPR) peak in the visible range for biomarker detection. The colour of the GNR can be tuned by the reaction conditions to provide multi-coloured gold nanorod conjugates. These antibody functionalized GNR have the potential to provide significant improvements in multiplexed analysis and sensitivity compared to conventional gold nanoparticle based lateral flow assays. However, a major challenge is the synthesis of stable conjugates that resist aggregation in samples with high ionic strength, (e.g. salt solutions) and allow highly sensitive detection of proteins. A detailed investigation of different reagents for the functionalization of gold nanorod materials are reported. An antibody modified GNR based lateral flow assay is validated for the determination of C-reactive Protein (CRP).

Improving Cell Penetration of Gold Nanorods by Using an Amphipathic Arginine Rich Peptide.

IntroductionGold nanorods are highly reactive, have a large surface-to-volume ratio, and can be functionalized with biomolecules. Gold nanorods can absorb infrared electromagnetic radiation, which is subsequently dispersed as local heat. Gold nanoparticles can be used as powerful tools for the diagnosis and therapy of different diseases. To improve the biological barrier permeation of nanoparticles with low cytotoxicity, in this study, we conjugated gold nanorods with cell-penetrating peptides (oligoarginines) and with the amphipathic peptide CLPFFD.MethodsWe studied the interaction of the functionalized gold nanorods with biological membrane models (liposomes) by dynamic light scattering, transmission electron microscopy and the Langmuir balance. Furthermore, we evaluated the effects on cell viability and permeability with an MTS assay and TEM.Results and DiscussionThe interaction study by DLS, the Langmuir balance and cryo-TEM support that GNR-Arg7CLPFFD enhances the interactions between GNRs and biological membranes. In addition, cells treated with GNR-Arg7CLPFFD internalized 80% more nanoparticles than cells treated with GNR alone and did not induce cell damage.ConclusionOur results indicate that incorporation of an amphipathic sequence into oligoarginines for the functionalization of gold nanorods enhances biological membrane nanoparticle interactions and nanoparticle cell permeability with respect to nanorods functionalized with oligoarginine. Overall, functionalized gold nanorods with amphipathic arginine rich peptides might be candidates for improving drug delivery by facilitating biological barrier permeation.

Hyaluronic acid functionalized gold nanorods combined with copper-based therapeutic agents for chemo-photothermal cancer therapy.

We herein report a hybrid nanocomposite (AuNRs-CTN@THA) which is based on hyaluronic acid-coated gold nanorods with loading of a copper complex through strong bonds. AuNRs-CTN@THA exhibits durable photothermal conversion capacity for pH-dominant and pH/temperature dual sensitive drug release, accomplishing synergetic antitumor efficacy and deep tumor penetration.

Salt Mediated Self-Assembly of Poly(ethylene glycol)-Functionalized Gold Nanorods

Although challenging, assembling and orienting non-spherical nanomaterials into two- and three-dimensional (2D and 3D) ordered arrays can facilitate versatile collective properties by virtue of their shape-dependent properties that cannot be realized with their spherical counterparts. Here, we report on the self-assembly of gold nanorods (AuNRs) into 2D films at the vapor/liquid interface facilitated by grafting them with poly(ethylene glycol) (PEG). Using surface sensitive synchrotron grazing incidence small angle X-ray scattering (GISAXS) and specular X-ray reflectivity (XRR), we show that PEG-AuNRs in aqueous suspensions migrate to the vapor/liquid interface in the presence of salt, forming a uniform monolayer with planar-to-surface orientation. Furthermore, the 2D assembled PEG functionalized AuNRs exhibit short range order into rectangular symmetry with side-by-side and tail-to-tail nearest-neighbor packing. The effect of PEG chain length and salt concentration on the 2D assembly are also reported.

Reversible end-to-end assembly of selectively functionalized gold nanorods by light-responsive arylazopyrazole-cyclodextrin interaction.

We propose a two-step ligand exchange for the selective end-functionalization of gold nanorods (AuNR) by thiolated cyclodextrin (CD) host molecules. As a result of the complete removal of the precursor capping agent cetyltrimethylammonium bromide (CTAB) by a tetraethylene glycol derivative, competitive binding to the host cavity was prevented, and reversible, light-responsive assembly and disassembly of the AuNR could be induced by host–guest interaction of CD on the nanorods and a photoswitchable arylazopyrazole cross-linker in aqueous solution. The end-to-end assembly of AuNR could be effectively controlled by irradiation with UV and visible light, respectively, over four cycles. By the introduction of AAP, previous disassembly limitations based on the photostationary states of azobenzenes could be solved. The combination photoresponsive interaction and selectively end-functionalized nanoparticles shows significant potential in the reversible self-assembly of inorganic–organic hybrid nanomaterials.

Detoxification and functionalization of gold nanorods with organic polymers and their applications in cancer photothermal therapy.

Gold nanorods (AuNRs) have attracted widespread attention in the last few decades due to their potential applications in cancer photothermal therapy (CPTT). However, the utilization of AuNRs is restricted because of their high toxicity for cells and tissues. Numerous methods have been developed to solve this problem, among which the most convenient one is to coat AuNRs with biocompatible materials or replace their original toxic surfactant such as the hexadecyl-trimethyl ammonium bromide (CTAB). Organic polymers (OPs) are intensively researched due to their low toxicity and easy access to modification with functional groups (e.g., targeting molecules), pharmaceuticals (e.g., chemo drugs) and imaging agents (e.g., radioactive elements). Herein, this mini review summarized recent progress in detoxification and functionalization of AuNRs exploiting OPs coatings and their applications in CPTT. To begin with, we introduced current major approaches used to modify AuNRs with typical OPs. Then, applications of OPs coated AuNRs in CPTT were discussed. At the end of the review, we proposed a brief outlook for the future development of modification and functionalization of AuNRs with organic materials.

Biocompatible and multifunctional gold nanorods for effective photothermal therapy of oral squamous cell carcinoma

Functionalized gold nanorods were successfully synthesized for the effective photothermal therapy of oral cancer.

Metal-Enhanced Near Infrared Fluorescence-Based Sensor with Highly Improved Sensitivity for Adenosine Triphosphate

Near infrared (NIR) fluorescent sensor for biologically important analyte is very promising because NIR fluorescence imaging has minimal autofluorescence and high tissue penetration in living system. Nevertheless, its low fluorescence quantum yield leads to low sensitivity of detection. In this study, a functionalized gold nanorods (NIR-AuNRs-3) plasmon enhanced NIR fluorescence-based sensor for adenosine triphosphate (ATP) was developed with highly improved sensitivity. The fluorescence quantum yield with ATP was significantly enhanced, from almost zero to 0.61, resulting in remarkable enhancement of sensitivity. This was attributed to the increase of radiative decay rate of NIR dye by 30-fold, along with almost unchanged nonradiative decay rate. The limit of detection for ATP was 0.6 nM, and it was successfully applied to determine low ATP levels (10.1 ± 2.6 nM) in rat brain. It has been also demonstrated to be useful for monitoring intracellular ATP levels with high sensitivity.

Folic Acid-Functionalized Gold Nanorods for Controlled Paclitaxel Delivery: In Vitro Evaluation and Cell Studies.

Short gold nanorods were synthesized (average length 28.08nm, average aspect ratio 3.54), which were functionalized with folic acid (FA) and 8-mercaptooctanoic acid (MOA) or 11-mercaptoundecanoic acid (MDA) and loaded with paclitaxel (PCT). FA was conjugated to the nanorods in order to render them targetable for cancer cells overexpressing folate receptors whereas MOA or MDA was attached on the nanorods in order to generate extra hydrophobic areas for entrapment of hydrophobic drugs such as PCT in the nanorods and in order to provide free carboxylic groups, which would allow for the conjugation of drug or other biofunctional molecules to the nanorods. The functionalized gold nanorods (GNRs-MOA-FA and GNRs-MDA-FA) did not exhibit any significant degree of aggregation in cell culture medium and blood plasma even after a prolonged incubation period of 7days, indicating the adequate colloidal stability of the nanorods in these media. The functionalized nanorods exhibited satisfactory entrapment efficiency (around 40%) for PCT and released less than 25% of their PCT content in phosphate buffer pH 7.4 in 48h. PCT entrapment efficiency was a little higher and PCT release rate a little lower in the GNRs-MOA-FA. Molecular analysis (qPCR) was used to find out that the MDA-MB-231 cancer cell line expresses the folate receptor (FL1R) whereas the MCF-7 cancer cell line does not. The PCT-loaded GNRs-MOA-FA were more cytotoxic than the PCT-loaded GNRs-MOA nanorods against the MDA-MB-231 cells, which probably relates to the higher uptake of the GNRs-MOA-FA nanorods by these cells. The opposite was true in the case of the MCF-7 cells.

A dual-targeted hyaluronic acid-gold nanorod platform with triple-stimuli responsiveness for photodynamic/photothermal therapy of breast cancer

Multi-stimuli-responsive theranostic nanoplatform integrating functions of both imaging and multimodal therapeutics holds great promise for improving diagnosis and therapeutic efficacy. In this study, we reported a pH, glutathione (GSH) and hyaluronidase (HAase) triple-responsive nanoplatform for HER2 and CD44 dual-targeted and fluorescence imaging-guided PDT/PTT dual-therapy against HER2-overexpressed breast cancer. The nanoplatform was fabricated by functionalizing gold nanorods (GNRs) with hyaluronic acid (HA) bearing pendant hydrazide and thiol groups via Au-S bonds, and subsequently chemically conjugating 5-aminolevulinic acid (ALA), Cy7.5 and anti-HER2 antibody onto HA moiety for PDT, fluorescence imaging and active targeting, respectively. The resulting versatile nanoplatform GNR-HA−ALA/Cy7.5-HER2 had uniform sizes, favorable dispersibility, as well as pH, GSH and HAase triple-responsive drug release manner. In vitro studies demonstrated that HER2 and CD44 receptor-mediated dual-targeting strategy could significantly enhance the cellular uptake of GNR-HA−ALA/Cy7.5-HER2. Under near-infrared (NIR) irradiation, MCF-7 cells could efficiently generate reactive oxygen species (ROS) and heat, and be more efficiently killed by a combination of PDT and PTT as compared with individual therapy. Pharmacokinetic and biodistribution studies showed that the nanoplatform possessed a circulation half-life of 1.9 h and could be specifically delivered to tumor tissues with an accumulation ratio of 12.8%. Upon the fluorescence imaging-guided PDT/PTT treatments, the tumors were completely eliminated without obvious side effects. The results suggest that the GNR-HA−ALA/Cy7.5-HER2 holds great potential for breast cancer therapy. Statement of significanceA combination of photodynamic therapy (PDT) and photothermal therapy (PTT) is emerging as a promising cancer treatment strategy. However, its therapeutic efficacy is compromised by the nonspecific delivery and unintended release of photo-responsive agents. Herein, we developed a multifunctional theranostic nanoplatform GNR-HA−ALA/Cy7.5-HER2 with pH, glutathione and hyaluronidase triple-responsive drug release for HER2 and CD44 dual-targeted and fluorescence imaging-guided PDT/PTT therapy against breast cancer. We demonstrated that HER2 and CD44 receptors-mediated dual-targeting strategy significantly enhanced the cellular uptake of GNR-HA−ALA/Cy7.5-HER2. We also demonstrated that the combined PDT/PTT treatment had significantly superior antitumor effect than PDT or PTT alone both in vitro and in vivo. Therefore, GNR-HA−ALA/Cy7.5-HER2 could serve as a promising nanoplatform for HER2-positive breast cancer therapy.