Efficient Photothermal Sensor Based on Coral-Like Hollow Gold Nanospheres for the Sensitive Detection of Sulfonamides.

Gold nanoparticles (AuNPs), universally regarded as colorimetric signal reporters, are widely employed in lateral flow immunoassays (LFIAs). However, it is difficult for AuNPs-LFIA to achieve a wide range and sensitive detection. Herein, novel coral-like hollow gold nanospheres (CHGNPs) are synthesized. The growth of gold nanospheres can be regulated to obtain a multibranched and hollow construction. The obtained CHGNPs possess intense broadband absorption across the visible to near-infrared region, exhibiting a high molar extinction coefficient of 14.65 × 1011 M-1 cm-1 and a photothermal conversion efficiency of 79.75%. Thus, the photothermal/colorimetric dual-readout LFIA is developed based on CHGNPs (CHGNPs-PT-LFIA and CHGNPs-CM-LFIA) to effectively improve the detection sensitivity and broaden the detection range in regard to sulfonamides (SAs). The limits of detection of the CHGNPs-PT-LFIA and CHGNPs-CM-LFIA reached 1.9 and 2.8 pg mL-1 for the quantitative detection of sulfaquinoxaline, respectively, which are 6.3-fold and 4.3-fold lower than that of the AuNPs-LFIA. Meanwhile, the CHGNPs-PT-LFIA broadened the detection range to three orders of magnitude, which ranged from 2.5 to 5000 pg mL-1. The synthesized photothermal CHGNPs have been proven effective in improving the performance of the LFIA and provide a potential option for the construction of sensing platforms.

Preparation of novel cisplatin-conjugated hollow gold nanospheres for targeting cervical cancer.

Cervical cancer is a deadly gynecological malignancy in need of innovative treatment strategies. Emerging preclinical data has suggested the benefits of nanocarriers over the traditional chemotherapy for cancer treatment. In particular, gold nanoparticles are gaining popularity due to gold's inert nature, limited side effects, good cytocompatibility, and flexibility in preparation/modification. We conjugated polyethylene glycol (PEG) with hollow gold nanospheres (HGNs) and loaded the pegylated HGNs with an anticancer drug, cisplatin to target cervical cancer. HGNs were irradiated with noninfrared laser to increase the penetration of drug into tumor tissue and improve the delivery of cisplatin. We investigated the comparative characterization studies of prepared cisplatin loaded pegylated HGNs (cis PEG-HGNs), free cisplatin, cisplatin loaded HGNs (cis-HGNs), cis PEG-HGNs without laser, and cis PEG-HGNs with laser and its effects over cervical cancer cells. Transmission electron microscopy photomicrographs confirmed the integrity of prepared HGNs. While no significant difference was observed between encapsulation efficiency and drug loading of cis-HGNs (84.6%) and cis PEG-HGNs (86.7%), the encapsulation efficiency increased almost twice in HGNs, compared with control gold nanoparticles (GNs) because of the hollow cavity in HGNs. In-vitro cytotoxicity was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay using HeLa cells. With irradiation, HGNs induced much elevated cytotoxicity. Not only HGNs were internalized by HeLa cells, they were retained in the cellular compartment. We also tested formulations in vivo and observed that the irradiated cis-HGNs and cis PEG-HGNs were most effective in regressing tumors in mice.

PEGylated hollow gold nanoparticles for combined X-ray radiation and photothermal therapy in vitro and enhanced CT imaging in vivo.

Up until now, hollow gold nanoparticles (HGNPs) with a spherical cavity have garnered much interest as theranostic agents in cancer therapy due to their high X-ray absorption and photothermal conversion ability. Herein, we describe the design of PEGylated hollow gold nanoparticles (mPEG@HGNPs) for combined X-ray radiation and photothermal therapy in vitro and enhanced computed tomography (CT) imaging in vivo using a breast tumor model. In vitro results revealed that mPEG@HGNPs could achieve a synergistic antitumor effect when irradiated by combined X-ray radiation and 808 nm near infrared laser light. Furthermore, mPEG@HGNPs exhibited a favorable tumor targeting effect and good CT contrast enhancement in both xenografted and orthotopic breast tumor models, due to the stealth effect of PEG which increased the enhanced permeability and retention (EPR) effect. These results suggest that mPEG@HGNPs may serve as multifunctional nanocomposites for cancer combination therapy and, thus, should be further studied.

Simple and Rapid High-Yield Synthesis and Size Sorting of Multibranched Hollow Gold Nanoparticles with Highly Tunable NIR Plasmon Resonances.

Branched gold nanoparticles with sharp tips are considered excellent candidates for sensing and field enhancement applications. Here, a rapid and simple synthesis strategy is presented that generates highly branched gold nanoparticles with hollow cores and a ca.100% yield through a simple one-pot seedless reaction at room temperature in the presence of Triton X-100. It is shown that multibranched hollow gold nanoparticles of tunable dimensions, branch density and branch length can be obtained by adjusting the concentrations of the reactants. Insights into the formation mechanism point toward an aggregative type of growth involving hollow core formation first, and branching thereafter. The pronounced near-infrared (NIR) plasmon band of the nanoparticles is due to the combined contribution from hollowness and branching, and can be tuned over a wide range (≈700-2000 nm). It is also demonstrated that the high environmental sensitivity of colloidal dispersions based on multibranched hollow gold nanoparticles can be boosted even further by separating the nanoparticles into fractions of given sizes and improved monodispersity by means of a glycerol density gradient. The possibility to obtain highly monodisperse multibranched hollow gold nanoparticles with predictable dimensions (50-300 nm) and branching and, therefore, tailored NIR plasmonic properties, highlights their potential for theranostic applications.

A One Step Strategy Based on Hollow Gold Nanoparticles to Detect C-Reactive Protein with High Sensitivity (Hs-CRP) in Serum for Monitoring Cardiovascular Disease.

Purpose: Rapid detection and diagnosis of diseases facilitate timely and effective treatment of cardiovascular diseases (CVD). The establishment of a one-step rapid detection method provides a new method for the initial screening and disease risk assessment of patients with cardiovascular diseases in primary medical units. Methods: Hollow gold nanoparticles (HGNPs) were synthesized using a cobalt template method followed by use as signal amplification probes for ultra-sensitive quantitative detection of serum C-reactive protein (CRP). To induce the localized surface plasmon resonance (LSPR) and improve protein labeling efficiency, we developed a sensitive detection mode by coating polyvinylpyrrolidone (PVP-K30) on the HGNPs, resulting in a significant improvement in detection performance. Results: Compared to traditional colloidal GNP-based LFTA, PVP-coated HGNPs exhibit a lower visual detection limit of 1 ng/mL, which a 25-fold decrement compare to using GNPs as the antibody-labeled probe, and the detection limit could be reduced to 0.14 ng/mL under the quantitative instrument. Conclusion: The one-step method based on HGNP immunochromatographic strips modified with PVP established in this study can be used for the detection of CRP and hs-CRP in biological samples. The performance of the immunochromatographic technique designed in this study was evaluated from the perspective of synthetic markers, and the application conditions of this strip were screened, verifying its high specificity, indicating that it has high sensitivity and strong detection limit compared to colloidal gold. The sensitivity of the hollow gold immunochromatographic test strip in this article has been increased by about 25 times, providing a new method for rapid detection of CVD in clinical diagnosis.

α-Lipoic acid loaded hollow gold nanoparticles designed for osteoporosis treatment: preparation, characterization and in vitro evaluation.

Osteoporosis is a common disease among the ageing society. Oxidative stress caused by excessive accumulation of reactive oxygen species (ROS) is the aetiology of osteoporosis. α-Lipoic acid (ALA) is an antioxidant in the body, which can eliminate excess ROS in the body and inhibits levels of oxidative stress in cells. Herein, we designed PEGylated hollow gold nanoparticles (HGNPs) loaded with ALA (mPEG@HGNPs-ALA) to remove ROS in the treatment of osteoporosis. First, mPEG@HGNPs with a particle size of ∼63 nm has been successfully synthesized. By comparing the drug loading of mPEG@HGNPs, it was concluded that the optimal mass ratio of mPEG@HGNPs (calculated by the amount of gold) to ALA was ∼1:2. ABTS antioxidant assay showed that free radical removal ability. In vitro results revealed that the preparation had good biocompatibility. At the gold concentration of 1-150 µg/mL, the cell viability of mPEG@HGNPs was more than 100%, which indicated that it could promote the proliferation of osteoblasts. What's more, mPEG@HGNPs-ALA could effectively remove the ROS caused by H2O2 injury and improve the cell viability. According to these results, it can be considered that mPEG@HGNPs-ALA has the potential to treat osteoporosis.

Synthesis of Hollow Gold Nanoparticles - Impact of Variables on Process Optimization.

Hollow gold nanoparticles (HAuNPs) are gold nanostructures with hollow interior. These particles have attracted a lot of interest due their excellent physicochemical and optical properties and their potential applications in diagnostics, sensing, imaging and assisting in tumor tracing and evaluating the effect of chemotherapy on tumor size, drug delivery and photothermal therapy. Sacrificial galvanic replacement using cobalt core is the most commonly used method for synthesis of HAuNPs. However, lack of reproducibility in synthesizing particles with desired surface plasmon resonance (SPR) is one of the major concerns for clinical application of these particles. In this work, we have identified and categorized various factors that could affect uniformity of cobalt core and subsequent formation of gold shell. Using slight modifications in the method, we have been able to synthesize HAuNPs with SPR in near infrared region at 808 nm with size of particles around 50-80 nm. HAuNPs can be further functionalized with suitable ligands like glutathione, polyethylene glycol, nucleic acids, sugars, fatty acids, proteins and peptides to promote enhanced permeability and retention in cancer cells and thus can serve as potential candidates in treatment of cancer.

Elucidating a Thermoresponsive Multimodal Photo-Chemotherapeutic Nanodelivery Vehicle to Overcome the Barriers of Doxorubicin Therapy.

In an attempt to circumvent the major pitfalls associated with conventional chemotherapy including drug resistance and off-target toxicity, we have adopted a strategy to simultaneously target both mitochondrial DNA (Mt-DNA) and nuclear DNA (n-DNA) with the aid of a targeted theranostic nanodelivery vehicle (TTNDV). Herein, folic acid-anchored p-sulfo-calix[4]arene (SC4)-capped hollow gold nanoparticles (HGNPs) were meticulously loaded with antineoplastic doxorubicin (Dox) and its mitochondrion-targeted analogue, Mt-Dox, in a pretuned ratio (1:100) for sustained thermoresponsive release of cargo. This therapeutic strategy was enabled to eradicate both n-DNA and Mt-DNA leaving no space to develop drug resistance. The SC4-capped HGNPs (HGNPSC4) were experimented for the first time as a photothermal (PTT) agent with 61.6% photothermal conversion efficiency, and they generated tunable localized heat more efficiently than bare HGNPs. Moreover, the cavity of SC4 facilitated the formation of an inclusion complex with folic acid to target the folate receptor expressing cancer cells and imparted enhanced biocompatibility. The as-synthesized TTNDV was demonstrated to be an ideal substrate for surface-enhanced Raman scattering (SERS) to monitor the molecular-level therapeutic progression in cells and a spheroidal model. A significant reduction in the tumor mass with a marked survival benefit was achieved in syngraft murine models through this synergistic photo-chemotherapy. Collectively, this multifunctional nanoplatform offers a robust approach to treat cancer without any scope of generating Dox resistance and off-target toxicity.

Customized hybrid and NIR-light triggered thermoresponsive drug delivery microparticles synthetized by photopolymerization in a one-step flow focusing continuous microreactor.

Photopolymerization is a selective technique that takes advantage of light-sensitive molecules to initiate and propagate monomeric structures to render covalently bonded macromolecular materials structures known as polymers. Herein, we present a novel one-step microfluidic synthesis of customized hybrid-thermoresponsive Poly(N-isopropylacrylamide) (PNIPAm) based microparticles (MPs) containing plasmonic hollow gold nanoparticles (HGNPs) and bupivacaine (BVP) used as a model drug. Those hybrid microparticles were prepared using a flow-focusing microreactor coupled to a UV LED device built with a simple outer PTFE tubing and an inner flexible capillary. Different tubing characteristics and flow rate ratios were altered in order to control the size of the resulting microparticles. In addition, components such as monomer, crosslinker and photoinitiator concentrations, as well as LED intensity and irradiation time were tuned to obtain different MPs and their characteristics and polymerization rates were compared by Gel Permeation Chromatography (GPC). Thermoresponsive properties were analyzed and the presence of HGNPs was confirmed in light-activated triggered drug release applications. Bupivacaine loading and release studies were evaluated with the resulting hollow and solid microparticles (which were obtained depending on the polymerization rate used) and their temperature responsiveness was assessed using a NIR laser when HGNPs were present in the constructs. Finally, cytotoxicity studies, cell-cycle arrest and apoptotic induction were carried out to certify their suitability for further biomedical applications to be used as triggerable drug depots.

Gold nanoparticles for the in situ polymerization of near-infrared responsive hydrogels based on fibrin.

Non-invasiveness and relative safety of photothermal therapy, which enables local hyperthermia of target tissues using a near infrared (NIR) laser, has attracted increasing interest. Due to their biocompatibility, amenability of synthesis and functionalization, gold nanoparticles have been investigated as therapeutic photothermal agents. In this work, hollow gold nanoparticles (HGNP) were coated with poly-l-lysine through the use of COOH-Poly(ethylene glycol)-SH as a covalent linker. The functionalized HGNP, which peak their surface plasmon resonance at 800 nm, can bind thrombin. Thrombin-conjugated HGNP conduct in situ fibrin polymerization, facilitating the process of generating photothermal matrices. Interestingly, the metallic core of thrombin-loaded HGNP fragmentates at physiological temperature. During polymerization process, matrices prepared with thrombin-loaded HGNP were loaded with genetically-modified stem cells that harbour a heat-activated and ligand-dependent gene switch for regulating transgene expression. NIR laser irradiation of resulting cell constructs in the presence of ligand successfully triggered transgene expression in vitro and in vivo. STATEMENT OF SIGNIFICANCE: Current technological development allows synthesis of gold nanoparticles (GNP) in a wide range of shapes and sizes, consistently and at scale. GNP, stable and easily functionalized, show low cytotoxicity and high biocompatibility. Allied to that, GNP present optoelectronic properties that have been exploited in a range of biomedical applications. Following a layer-by-layer functionalization approach, we prepared hollow GNP coated with a positively charged copolymer that enabled thrombin conjugation. The resulting nanomaterial efficiently catalyzed the formation of fibrin hydrogels which convert energy of the near infrared (NIR) into heat. The resulting NIR-responsive hydrogels can function as scaffolding for cells capable of controlled gene expression triggered by optical hyperthermia, thus allowing the deployment of therapeutic gene products in desired spatiotemporal frameworks.

Cisplatin-loaded hollow gold nanoparticles for laser-triggered release.

BACKGROUND: Hollow gold nanoparticles (HGNPs) exposed to near-infrared (NIR) light yield photothermal effects that can trigger a variety of biological effects for potential biomedical applications. However, the mechanism of laser-triggered drug release has not been studied before. METHODS: A tripeptide Ac-Glu-Glu-Cys-NH2 (Ac-EEC) was directly linked to the surface of HGNPs. The EEC-HGNPs conjugate was then complexed with cisplatin Pt(II) to give Ac-EEC(Pt)-HGNPs. Folic acid was introduced to the gold surface of Ac-EEC-HGNPs through a thioctic acid-terminated polyethylene glycol linker (F-PEG-TA) followed by complexation with Pt(II) to give F-Ac-EEC(Pt)-HGNPs. Laser treatment was instituted with a 15-ns pulsed laser at a repetition rate of 10 Hz. The released Pt(II) was quantified by inductively coupled plasma mass spectroscopy, and the nature of the released Pt-containing species was characterized by liquid chromatography-mass spectroscopy. The cytotoxicity was studied using the MTT assay. RESULTS: Pt(II) was released from Ac-EEC(Pt)-HGNPs via two modes: (1) sustained release through an inverse ligand exchange reaction with chloride ions and (2) rapid release through cleavage of the Au-S bond between the tripeptide linker and Au surface upon NIR laser irradiation. The folate (F) conjugate of the nanoconstruct, F-Ac-EEC(Pt)-HGNPs, in combination with laser treatment showed a significantly greater effect on cell mortality against folate-overexpressing human epidermoid carcinoma KB cells than F-Ac-ECC(Pt)-HGNPs alone after 24 h of incubation. CONCLUSIONS: These results demonstrate that the photothermal property of HGNPs can be used for dual-modality photothermal therapy and NIR laser-triggered platinum-based chemotherapy.

A sensitive SPR biosensor based on hollow gold nanospheres and improved sandwich assay with PDA-Ag@Fe3O4/rGO.

A novel surface plasmon resonance (SPR) biosensor based on hollow gold nanospheres (HGNPs) and an improved sandwich assay was developed to detect rabbit IgG. The electromagnetic coupling between the HGNPs and Au film, and the notable plasmonic fields spread over the inner and outer surfaces of HGNPs, led to the considerable amplification of the SPR signal. Polydopamine-Ag@Fe3O4/reduced graphene oxide (PDA-Ag@Fe3O4/rGO) was introduced to bind detection antibody (Ab2) to form the improved sandwich structure. Ag nanoparticles were excited to produce SPR and their hot electrons were doped on graphene thin films, which amplified the response of biomolecules. Magnetic nanoparticles (Fe3O4) simplified the collection of Ab2-PDA-Ag@Fe3O4/rGO. An external layer of polydopamine (PDA) permitted the efficient immobilization of Ab2 without activation via abundant functional groups and protected the nanoparticles from etching or agglomeration. In addition, because of its large mass, Ab2-PDA-Ag@Fe3O4/rGO also played a key role in the further amplification of the SPR response signals. This novel SPR biosensor exhibited an effective response to the rabbit IgG at the different concentrations ranging from 0.019 to 40.00µgmL-1. This value is 132 times lower than that observed for a traditional SPR biosensor based on Au-3-mercaptopropionic acid and 8 times lower than that obtained from an Ab2 sandwich assay, which indicates that the SPR sensor has high sensitivity. In addition, the designed biosensor showed satisfactory recoveries to detect the rabbit IgG spiked in serum samples. Therefore, the novel SPR biosensor with high sensitivity and acceptable recovery has potential for practical applications.

A green and facile preparation approach, licochalcone A capped on hollow gold nanoparticles, for improving the solubility and dissolution of anticancer natural product.

This study described a valuable drug delivery system for poorly water-soluble anticancer naturalproduct, licochalcone A, isolated from Glycyrrhiza inflata, loaded on hollow gold nanoparticles by green method to improve solubility and dissolution and maintain its natural pharmacological property. Briefly, the formation of hollow gold nanoparticles involves three steps: preparing of silica nanospheres by Stober method, forming of a thick gold shell around the silica templates and etching of silica particles by HF solution. Hollow gold nanoparticles (HGNPs) and drug loaded hollow gold nanoparticles (L-HGNPs) displayed spherical structure and approximately 200nm in size observed by SEM, XRD, EDS and DSC analysis showed that HGNPs were gold hollow structure and crystalline form. The solubility in aqueous solution of licochalcone A was increased obviously to 488.9 µg/ml, compared with free drugs of 136.1 µg/ml. Another interesting finding is that near-infrared (NIR) irradiation increased the speed of solubility of licochalcone A in aqueous solutions, rather than quantity. In short, the method of nano-delivery system combined with poorly water-soluble drug to improve its solubility and dissolution is worth applying to other natural products in order to increase their opportunities in clinical applications.

Xanthoceraside hollow gold nanoparticles, green pharmaceutics preparation for poorly water-soluble natural anti-AD medicine.

In order to increase the solubility of poorly water-soluble natural product, xanthoceraside, an effective anti-AD compound from Xanthoceras sorbifolia Bunge, and maintain its natural property, the xanthoceraside hollow gold nanoparticles were successively prepared by green ultrasonic method with silica spheres as templates and HF solution as selective etching solvent. Hollow gold nanoparticles and drug-loaded hollow gold nanoparticles were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and differential scanning calorimetry (DSC). The solubilities of xanthoceraside loaded on hollow gold nanoparticles were increased obviously from 3.0µg/ml and 2.5µg/ml to 12.7µg/ml and 10.7µg/ml at 25°C and 37°C, respectively. The results of XRD and DSC indicated that the reason for this increase was mainly due to the amorphous state of xanthoceraside loaded on the hollow gold nanoparticles. In summary, the method of loading xanthoceraside onto hollow gold nanoparticles was a green and useful strategy to improve the solubility and dissolution of poorly water-soluble natural products and worth to applying to other natural products.

Highly sensitive and selective detection of dopamine based on hollow gold nanoparticles-graphene nanocomposite modified electrode.

Highly dispersed hollow gold-graphene (HAu-G) nanocomposites were synthesized by a two-step method. The immobilization of hollow gold nanoparticles (HAu NPs) onto the surface of graphene sheets was achieved by mixing an aqueous solution of HAu NPs with a poly(N-vinylpyrrolidone)-functionalized graphene dispersion at room temperature. A glassy carbon electrode (GCE) was modified with the nanocomposites, and the as-prepared modified electrode displayed high electrocatalytic activity and extraordinary electronic transport properties. Amperometric detection of dopamine (DA) performed with the HAu-G modified electrode exhibits a good linearity between 0.08 and 600 µM with a low detection limit of 0.05 µM (S/N=3) and also possesses good reproducibility and operational stability. The interference of ascorbic acid (AA) and uric acid (UA) can be excluded when using differential pulse voltammetric technique. In addition, this type of modified electrode can also be applied to the determination of DA content in dopamine hydrochloride injection. It is obvious that the HAu-G modified electrode provides a new way to detect dopamine sensitively and selectively.