Gold Nanoparticles For Delivery Research Articles

Enhancement of radiation effect on cancer cells by gold-pHLIP

Previous research has shown that gold nanoparticles can increase the effectiveness of radiation on cancer cells. Improved radiation effectiveness would allow lower radiation doses given to patients, reducing adverse effects; alternatively, it would provide more cancer killing at current radiation doses. Damage from radiation and gold nanoparticles depends in part on the Auger effect, which is very localized; thus, it is important to place the gold nanoparticles on or in the cancer cells. In this work, we use the pH-sensitive, tumor-targeting agent, pH Low-Insertion Peptide (pHLIP), to tether 1.4-nm gold nanoparticles to cancer cells. We find that the conjugation of pHLIP to gold nanoparticles increases gold uptake in cells compared with gold nanoparticles without pHLIP, with the nanoparticles distributed mostly on the cellular membranes. We further find that gold nanoparticles conjugated to pHLIP produce a statistically significant decrease in cell survival with radiation compared with cells without gold nanoparticles and cells with gold alone. In the context of our previous findings demonstrating efficient pHLIP-mediated delivery of gold nanoparticles to tumors, the obtained results serve as a foundation for further preclinical evaluation of dose enhancement.

In vivo gold nanoparticle delivery of peptide vaccine induces anti-tumor immune response in prophylactic and therapeutic tumor models.

Gold nanoparticles (AuNPs) are promising vehicles for cancer immunotherapy, with demonstrated efficacy in immune delivery and innate cell stimulation. Nevertheless, their potential has yet to be assessed in the in vivo application of peptide cancer vaccines. In this study, it is hypothesized that the immune distribution and adjuvant qualities of AuNPs could be leveraged to facilitate delivery of the ovalbumin (OVA) peptide antigen and the CpG adjuvant and enhance their therapeutic effect in a B16-OVA tumor model. AuNP delivery of OVA (AuNP-OVA) and of CpG (AuNP-CpG) enhanced the efficacy of both agents and induced strong antigen-specific responses. In addition, it is found that AuNP-OVA delivery alone, without CpG, is sufficient to promote significant antigen-specific responses, leading to subsequent anti-tumor activity and prolonged survival in both prophylactic and therapeutic in vivo tumor models. This enhanced therapeutic efficacy is likely due to the adjuvant effect of peptide coated AuNPs, as they induce inflammatory cytokine release when cultured with bone marrow dendritic cells. Overall, AuNP-mediated OVA peptide delivery can produce significant therapeutic benefits without the need of adjuvant, indicating that AuNPs are effective peptide vaccine carriers with the potential to permit the use of lower and safer adjuvant doses during vaccination.

Intratracheal Delivery of Gold Nanoparticles for Radiation Therapy in Murine Lung Adenocarcinoma

Intratracheal Delivery of Gold Nanoparticles for Radiation Therapy in Murine Lung Adenocarcinoma

Severe myotonia in juvenile myotonic dystrophy type 2 and sodium channel gene mutation

Severe myotonia in juvenile myotonic dystrophy type 2 and sodium channel gene mutation

Development and testing of gold nanoparticles for drug delivery and treatment of heart failure: a theranostic potential for PPP cardiology

IntroductionNanoscale gold particles (AuNPs) have wide perspectives for biomedical applications because of their unique biological properties, as antioxidative activity and potentials for drug delivery.Aims and objectivesThe aim was to test effects of AuNPs using suggested heart failure rat model to compare with proved medication Simdax, to test gold nanoparticle for drug delivery, and to test sonoporation effect to increase nanoparticles delivery into myocardial cells.Material and methodsWe performed biosafety and biocompatibility tests for AuNPs and conjugate with Simdax. For in vivo tests, we included Wistar rats weighing 180–200 g (n = 54), received doxorubicin in cumulative dose of 12.0 mg/kg to model advance heart failure, registered by ultrasonography. We formed six groups: the first three groups of animals received, respectively, 0.06 ml Simdax, AuNPs, and conjugate (AuNPs-Simdax), intrapleurally, and the second three received them intravenously. The seventh group was control (saline). We performed dynamic assessment of heart failure regression in vivo measuring hydrothorax. Sonoporation of gold nanoparticles to cardiomyocytes was tested.ResultsWe designed and constructed colloidal, spherical gold nanoparticles, AuNPs-Simdax conjugate, both founded biosafety (in cytotoxicity, genotoxicity, and immunoreactivity). In all animals of the six groups after the third day post-medication injection, no ascites and liver enlargement were registered (P < 0.001 vs controls). Conjugate injection showed significantly higher hydrothorax reduction than Simdax injection only (P < 0.01); gold nanoparticle injection showed significantly higher results than Simdax injection (P < 0.05). AuNPs and conjugate showed no significant difference for rat recovery. Difference in rat life continuity was significant between Simdax vs AuNPs (P < 0.05) and Simdax vs conjugate (P < 0.05). Sonoporation enhances AuNP transfer into the cell and mitochondria that were highly localized, superior to controls (P < 0.01 for both).ConclusionsGold nanoparticles of 30 nm and its AuNPs-Simdax conjugate gave positive results in biosafety and biocompatibility in vitro and in vivo. AuNPs-Simdax and AuNPs have similar significant cardioprotective effects in rats with doxorubicin-induced heart failure, higher than that of Simdax. Intrapleural (local) delivery is preferred over intravenous (systemic) delivery according to all tested parameters. Sonoporation is able to enhance gold nanoparticle delivery to myocardial cells in vivo.

Gold Nanoparticle Delivery of Modified CpG Stimulates Macrophages and Inhibits Tumor Growth for Enhanced Immunotherapy

Gold nanoparticle accumulation in immune cells has commonly been viewed as a side effect for cancer therapeutic delivery; however, this phenomenon can be utilized for developing gold nanoparticle mediated immunotherapy. Here, we conjugated a modified CpG oligodeoxynucleotide immune stimulant to gold nanoparticles using a simple and scalable self-assembled monolayer scheme that enhanced the functionality of CpG in vitro and in vivo. Nanoparticles can attenuate systemic side effects by enhancing CpG delivery passively to innate effector cells. The use of a triethylene glycol (TEG) spacer on top of the traditional poly-thymidine spacer increased CpG macrophage stimulatory effects without sacrificing DNA content on the nanoparticle, which directly correlates to particle uptake. In addition, the immune effects of modified CpG-AuNPs were altered by the core particle size, with smaller 15 nm AuNPs generating maximum immune response. These TEG modified CpG-AuNP complexes induced macrophage and dendritic cell tumor infiltration, significantly inhibited tumor growth, and promoted survival in mice when compared to treatments with free CpG.

Nanophotonics and Theranostics: Will Light Do the Magic?

Nanophotonics and Theranostics: Will Light Do the Magic?

PH (low) insertion peptides (pHLIPs) for delivery of gold nanoparticles to tumors

pH (low) insertion peptides (pHLIPs) for delivery of gold nanoparticles to tumors

PHLIP peptide targets nanogold particles to tumors

Progress in nanomedicine depends on the development of nanomaterials and targeted delivery methods. In this work, we describe a method for the preferential targeting of gold nanoparticles to a tumor in a mouse model. The method is based on the use of the pH Low Insertion Peptide (pHLIP), which targets various imaging agents to acidic tumors. We compare tumor targeting by nonfunctionalized nanogold particles with nanogold-pHLIP conjugates, where nanogold is covalently attached to the N terminus of pHLIP. Our most important finding is that both intratumoral and i.v. administration demonstrated a significant enhancement of tumor uptake of gold nanoparticles conjugated with pHLIP. Statistically significant reduction of gold accumulation was observed in acidic tumors and kidney when pH-insensitive K-pHLIP was used as a vehicle, suggesting an important role of pH in the pHLIP-mediated targeting of gold nanoparticles. The pHLIP technology can substantially improve the delivery of gold nanoparticles to tumors by providing specificity of targeting, enhancing local concentration in tumors, and distributing nanoparticles throughout the entire tumor mass where they remain for an extended period (several days), which is beneficial for radiation oncology and imaging.

Role of Antibody-Mediated Tumor Targeting and Route of Administration in Nanoparticle Tumor Accumulation in Vivo

In this study, we have looked at enhancing tumor uptake and intracellular delivery of gold nanoparticles (AuNPs) while reducing the systemic exposure by systematic evaluation of the impact of targeting and route of administration on organ distribution. High-resolution microSPECT/CT imaging was used to track the in vivo fate of (111)In-labeled nontargeted and human epidermal growth factor receptor-2 (HER-2) targeted AuNPs following intravenous (i.v.) or intratumoral (i.t.) injection. For i.v. injection, the effects of GdCl3 (for deactivation of macrophages) and nonspecific (anti-CD20) antibody rituximab (for blocking of Fc mediated liver and spleen uptake) were studied. It was found that HER-2 targeting via attachment of trastuzumab paradoxically decreased tumor uptake as a result of faster elimination of the targeted AuNPs from the blood while improving internalization in HER-2-positive tumor cells as compared to nontargeted AuNPs. I.T. injections with HER-2 targeted AuNPs resulted in high tumor retention with low systemic exposure and represents an attractive delivery strategy. Our results provide a strategy for optimizing tumor delivery and quantifying organ distribution of this widely studied class of nanomaterial.

Delivery of gold nanoparticles to the brain by conjugation with a peptide that recognizes the transferrin receptor

The treatment of Alzheimer's disease and many other brain-related disorders is limited because of the presence of the blood–brain barrier, which highly regulate the crossing of drugs. Metal nanoparticles have unique features that could contribute to the development of new therapies for these diseases. Nanoparticles have the capacity to carry several molecules of a drug; furthermore, their unique physico-chemical properties allow, for example, photothermal therapy to produce molecular surgery to destroy tumor cells and toxic structures. Recently, we demonstrated that gold nanoparticles conjugated to the peptide CLPFFD are useful to destroy the toxic aggregates of β-amyloid, similar to the ones found in the brains of patients with Alzheimer's disease. However, nanoparticles, like many other compounds, have null or very low capacity to cross the blood–brain barrier. In order to devise a strategy to improve drug delivery to the brain, here we introduced the peptide sequence THRPPMWSPVWP into the gold nanoparticle–CLPFFD conjugate. This peptide sequence interacts with the transferrin receptor present in the microvascular endothelial cells of the blood–brain barrier, thus causing an increase in the permeability of the conjugate in brain, as shown by experiments in vitro and in vivo. Our results are highly relevant for the therapeutic applications of gold nanoparticles for molecular surgery in the treatment of neurodegenerative diseases such as Alzheimer's disease.

Peptide‐mediated cell penetration and targeted delivery of gold nanoparticles into lysosomes

There is considerable interest in the sub-cellular targeting and delivery of biomolecules, therapeutic and imaging agents, and nanoparticles and nanoparticle conjugates into organelles for therapeutic and imaging purposes. To date, a number of studies have used sorting peptides for targeted delivery of cargo into different cell organelles but not into lysosomes. In this study, the delivery of 13-nm gold nanoparticles across the cell membrane followed by targeted localisation into the lysosomes of a mammalian cell line was examined using novel combinations of cell-penetrating peptides and lysosomal sorting peptides conjugated to the nanoparticles. Using a combination of fluorescence spectroscopy, fluorescence microscopy and transmission electron microscopy techniques, we show that these nanoconjugates were efficiently and selectively delivered into the lysosomes with minimal cytotoxic effects. This novel targeted delivery system may underpin the development of a new strategy for the treatment of lysosomal storage diseases by exploiting the large surface area of nanoparticles to deliver drugs or replacement enzymes directly to the lysosomes.

Use of fractional laser microablation and ultrasound to facilitate the delivery of gold nanoparticles into skin in vivo

The delivery of gold nanoparticles (nanocages coated with a layer of silicon dioxide (40/20 nm)) dispersed in the solution (glycerol + polyethylene glycol-400, 1 : 1) into the skin tissue is studied experimentally in vivo. From the data of optical coherence tomography and histochemical analysis it follows that simple application of suspension of nanoparticles is not efficient enough for delivery of the particles into the skin as a result of passive diffusion. It is shown that fractional laser microablation of skin before the application of the suspension, followed by the topical treatment by ultrasound allows penetration through the epidermis layer and delivery of nanoparticles into dermis and hypodermis

Caveolae-mediated endocytosis of biocompatible gold nanoparticles in living Hela cells **Dedicated to Professor Stuart M Lindsay on the occasion of his 60th birthday.

Efficient intracellular delivery of gold nanoparticles (AuNPs) and unraveling the mechanism underlying the intracellular delivery are essential for advancing the applications of AuNPs toward in vivo imaging and therapeutic interventions. We employed fluorescence microscopy to investigate the internalization mechanism of small-size AuNPs by living Hela cells. Herein, we found that the caveolae-mediated endocytosis was the dominant pathway for the intracellular delivery of small-size AuNPs. The intracellular delivery was suppressed when we depleted the cholesterol with methyl-β-cyclodextrin (MβCD); in contrast, the sucrose that disrupts the formation of clathrin-mediated endocytosis did not block the endocytosis of AuNPs. Meanwhile, we examined the intracellular localization of AuNPs in endocytic vesicles by fluorescent colocalization. This work would provide a potential technique to study the intracellular delivery of small-size nanoparticles for biomedical applications.

The improvement of anti-proliferation activity against breast cancer cell line of thioguanine by gold nanoparticles

Drug resistance and damage to non-malignant normal cells are the big medical challenges in cancer chemotherapy. As a currently in use anticancer drug, several side effects have been attributed to 6-Thioguanine (6TG). There are several options to help in minimizing or preventing the unwanted harmful effects of a drug. Loading of 6TG on the surface of gold nanoparticles (GNPs) which have unique physicochemical properties for transporting and unloading pharmaceuticals seems one of the useful strategies to overcome the deleterious effects of this anticancer drug. In the current study, GNPs with almost spherical morphology and the average diameter between 4 and 6 nm which is larger than the cutoff size of the renal system were used for functionalization with 6TG. In order to characterize shape and size of GNPs, as well as the percent entrapment efficiency of 6TG, transmission electron microscopy, UV/Vis spectroscopy, and thermal gravimetric analysis were applied. To estimate the improvement of the drug delivery of GNPs, breast cancer cells were treated with 6TG and 6TG-functionalized GNPs (6TG-GNPs), and cell viability was studied in vitro, by 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assay. As shown, both free 6TG and 6TG-GNP revealed anti-proliferation activity against the cancer cells in time- and dose-dependent manners. Moreover, 6TG-GNP displays significantly greater anti-proliferation activity than that of free 6TG in all incubation times and at the concentration of 12.5 μM and above. Overall, the improvement of anti-proliferation activity of 6TG-GNPs compared to that of 6TG can be attributed to enhanced intracellular uptake of the functionalized GNPs via the mechanism of endocytosis. Moreover, this study may suggest GNP as a useful carrier of 6TG against its several adverse effects in cancer therapy.

Enhanced delivery of gold nanoparticles with therapeutic potential into the brain using MRI-guided focused ultrasound

The blood brain barrier (BBB) is a major impediment to the delivery of therapeutics into the central nervous system (CNS). Gold nanoparticles (AuNPs) have been successfully employed in multiple potential therapeutic and diagnostic applications outside the CNS. However, AuNPs have very limited biodistribution within the CNS following intravenous administration. Magnetic resonance imaging guided focused ultrasound (MRgFUS) is a novel technique that can transiently increase BBB permeability allowing delivery of therapeutics into the CNS. MRgFUS has not been previously employed for delivery of AuNPs into the CNS. This work represents the first demonstration of focal enhanced delivery of AuNPs into the CNS using MRgFUS in a rat model both safely and effectively. Histologic visualization and analytical quantification of AuNPs within the brain parenchyma suggest BBB transgression. These results suggest a role for MRgFUS in the delivery of AuNPs with therapeutic potential into the CNS for targeting neurological diseases. From the Clinical EditorGold nanoparticles have been successfully utilized in experimental diagnostic and therapeutic applications; however, the blood-brain barrier (BBB) is not permeable to these particles. In this paper, the authors demonstrated that MRI guided focused ultrasound is capable to transiently open the BBB thereby enabling CNS access.

Delivery of Gold Nanoparticles Inside Carbon Nanotubes by Oligonucleotides

Delivery of gold nanoparticles with 2nm or so in diameter inside multiwall carbon nanotubes (MCNTs) by oligonucleotides was performed under the condition of 400k and 3bar for 20 min. The Au-oligo-CNT complexes were first purified via 1% agarose gel electrophoresis and then analyzed via high resolution transmission electron microscopy (HR-TEM) and energy dispersive X–ray spectroscopy (EDX). The results showed that the excess of oligonucleotides, Au nanopartilces and the Au-oligo hybrids attached to the outside walls of CNTs could be removed away by agarose gel electrophoresis. HR-TEM and EDX results demonstrated that 2% or so Au-oligo hybrids were successfully delivered inside MCNTs. In contrast, few Au nanopartilces were observed to locate inside CNTs under identical experimental conditions. This is the very first confirmation that oligonucleotides can be used to deliver Au nanoparticles inside MCNTs. The van der Waals attraction between CNT and Au-oligo hybrids is likely the main driving force for this phenomenon. This phenomenon has potential applications in future nanotechnology such as molecular electronics, biochemical sensors, nano-devices, gene storage and delivery systems.

125I-labeled gold nanorods for targeted imaging of inflammation.

For better examination of inflammation, we designed inflammation-targeted nuclear and optical dual-modality contrast agents prepared by I-125 radiolabeling of gold nanorods (GdNRs) conjugated with anti-intercellular adhesion molecule 1 (ICAM-1) antibody. The bioactivity and specific binding of the PEGylated (125)I-ICAM-GdNR conjugates to the ICAM-1 was validated through ELISA testing. Inflammation-targeted imaging was then conducted on an adjuvant-induced arthritic rat model which demonstrated an elevation of ICAM-1 level in the affected ankle joints. Facilitated by the I-125 radioisotope and the whole-body imaging via the Gamma camera, the time-dependent distribution of the systemically injected agent as well as the uptake of the agent in the inflammatory articular tissues could be examined conveniently and quantitatively. The success in targeted delivery of gold nanoparticles to inflammatory tissue enables both nuclear and optical imaging of inflammation at molecular or cellular level. Other than diagnosis, radiolabeled gold nanoparticles also hold promise for targeted therapy of a variety of disorders.

Efficient delivery of gold nanoparticles by dual receptor targeting.

Targeted delivery of inorganic nanoparticles, particularly of gold, may find wide utility in a number of biomedical applications due to their unique physicochemical and optoelectronic properties. [1-6] However, efficient delivery of a threshold amount of such particles is required for successful biomedical applications including imaging, detection/diagnosis and therapy. [7, 8] Efficient delivery of gold nanoparticles may be achieved by simultaneous targeting of multiple receptors on the cancer cells. [9] Hence, selection of appropriate targets is crucial for successful application of multiple/dual receptor targeted drug delivery system. Herein, we demonstrate the fabrication and characterization of gold nanoconjugates containing EGFR (epidermal receptor growth factor) and FR (folate receptor) antibodies on a single gold core, as a proof of principle study, to enhance the loading of gold nanoparticles (AuNPs) to EGFR and FR expressing cancer cells. We further demonstrate that the dual receptor targeted system (DRTS) is more efficient in delivering AuNPs to EGFR and FR expressing cancer cells than their corresponding single receptor targeting systems (SRTS). Such selective delivery of GNPs could be utilized in numerous biomedical applications such as detection, diagnosis and therapy. The folate receptor α (FRα) and epidermal growth factor receptor (EGFR) is known to be overexpressed in a number of malignancies including ovarian cancer. [10] Farletuzumab, a monoclonal antibody to FRα is in Phase III clinical trials both alone or in combination with platinum/taxane chemotherapy for the patients experiencing recurrence. [11] Several monoclonal antibodies directed against EGFR (trastuzumab, cetuximab, pertuzumab, and panitumumab) and small molecule tyrosine kinase inhibitors (erlotinib and gefitinib) have been investigated and are currently in different phases of clinical trials in ovarian cancer. [12] Thus, FR and EGFR represent important targets for tumor-specific delivery of anticancer drugs. Herein, we demonstrate, as a proof of principle study, fabrication and characterization of a dual receptor targeted system (DRTS) and demonstrate that it is much more efficient in delivering AuNPs to EGFR and FR expressing ovarian cancer cells Skov3-ip and OVCAR-5 than their corresponding single receptor targeting systems (SRTS). Such selective delivery of AuNPs has the potential to be used in numerous biomedical applications including detection, diagnosis and therapeutics.

Cellular Uptake and Fate of PEGylated Gold Nanoparticles Is Dependent on Both Cell-Penetration Peptides and Particle Size

Numerous studies have examined how the cellular delivery of gold nanoparticles (AuNPs) is influenced by different physical and chemical characteristics; however, the complex relationship between AuNP size, uptake efficiency and intracellular localization remains only partially understood. Here we examine the cellular uptake of a series of AuNPs ranging in diameter from 2.4 to 89 nm that are synthesized and made soluble with poly(ethylene glycol)-functionalized dithiolane ligands terminating in either carboxyl or methoxy groups and covalently conjugated to cell penetrating peptides. Following synthesis, extensive physical characterization of the AuNPs was performed with UV-vis absorption, gel electrophoresis, zeta potential, dynamic light scattering, and high resolution transmission electron microscopy. Uptake efficiency and intracellular localization of the AuNP-peptide conjugates in a model COS-1 cell line were probed with a combination of silver staining, fluorescent counterstaining, and dual mode fluorescence coupled to nonfluorescent scattering. Our findings show that AuNP cellular uptake is directly dependent on the surface display of the cell-penetrating peptide and that the ultimate intracellular destination is further determined by AuNP diameter. The smallest 2.4 nm AuNPs were found to localize in the nucleus, while intermediate 5.5 and 8.2 nm particles were partially delivered into the cytoplasm, showing a primarily perinuclear fate along with a portion of the nanoparticles appearing to remain at the membrane. The 16 nm and larger AuNPs did not enter the cells and were located at the cellular periphery. A preliminary assessment of cytotoxicity demonstrated minimal effects on cellular viability following peptide-mediated uptake.