Fong-Yu Cheng

Au nanorod design as light-absorber in the first and second biological near-infrared windows for in vivo photothermal therapy.

Photothermal cancer therapy using near-infrared (NIR) laser radiation is an emerging treatment. In the NIR region, two biological transparency windows are located in 650-950 nm (first NIR window) and 1000-1350 nm (second NIR window) with optimal tissue transmission obtained from low scattering and energy absorption, thus providing maximum radiation penetration through tissue and minimizing autofluorescence. To date, intensive effort has resulted in the generation of various methods that can be used to shift the absorbance of nanomaterials to the 650-950 nm NIR regions for studying photoinduced therapy. However, NIR light absorbers smaller than 100 nm in the second NIR region have been scant. We report that a Au nanorod (NR) can be designed with a rod-in-shell (rattle-like) structure smaller than 100 nm that is tailored to be responsive to the first and second NIR windows, in which we can perform hyperthermia-based therapy. In vitro performance clearly displays high efficacy in the NIR photothermal destruction of cancer cells, showing large cell-damaged area beyond the laser-irradiated area. This marked phenomenon has made the rod-in-shell structure a promising hyperthermia agent for the in vivo photothermal ablation of solid tumors when activated using a continuous-wave 808 m (first NIR window) or a 1064 nm (second NIR window) diode laser. We tailored the UV-vis-NIR spectrum of the rod-in-shell structure by changing the gap distance between the Au NR core and the AuAg nanoshell, to evaluate the therapeutic effect of using a 1064 nm diode laser. Regarding the first NIR window with the use of an 808 nm diode laser, rod-in-shell particles exhibit a more effective anticancer efficacy in the laser ablation of solid tumors compared to Au NRs.

Cytotoxicity, oxidative stress, apoptosis and the autophagic effects of silver nanoparticles in mouse embryonic fibroblasts

With the advancement of nanotechnology, nanomaterials have been comprehensively applied in our modern society. However, the hazardous impacts of nanoscale particles on organisms have not yet been thoroughly clarified. Currently, there exist numerous approaches to perform toxicity tests, but common and reasonable bio-indicators for toxicity evaluations are lacking. In this study, we investigated the effects of silver nanoparticles (AgNPs) on NIH 3T3 cells to explore the potential application of these nanoparticles in consumer products. Our results demonstrated that AgNPs were taken up by NIH 3T3 cells and localized within the intracellular endosomal compartments. Exposure to AgNPs is a potential source of oxidative stress, which leads to the induction of reactive oxygen species (ROS), the up-regulation of Heme oxygenase 1 (HO-1) expression, apoptosis and autophagy. Interestingly, AgNPs induced morphological and biochemical markers of autophagy in NIH 3T3 cells and induced autophagosome formation, as evidenced by transmission electron microscopic analysis, the formation of microtubule-associated protein-1 light chain-3 (LC3) puncta and the expression of LC3-II protein. Thus, autophagy activation may be a key player in the cellular response against nano-toxicity.

Near-Infrared Light-Responsive Intracellular Drug and siRNA Release Using Au Nanoensembles with Oligonucleotide-Capped Silica Shell

Taking advantage of the character of Au nanorods (NRs) to absorb NIR light, a NIR-responsive oligonucleotide-gated ensemble is developed to perform intracellular drug delivery. Using an oligonucleotide bio-gate enables siRNA release into cells for translational regulation as well as cytotoxicity in anti-cancer drug delivery.

Simple synthesis and functionalization of iron nanoparticles for magnetic resonance imaging.

Magnetic nanoparticles (NPs) are increasingly important in many biomedical applications, such as drug delivery, hyperthermia, and magnetic resonance imaging (MRI) contrast enhancement. For MRI, iron oxide NPs are the only commercial T2 or negative contrast agents, due to their biocompatibility and ease of synthesis and research in the area is highly active. The efficacy of these contrast agents depends mainly on the surface chemistry and magnetic properties of the NPs. Materials with larger magnetization could induce more efficient transverse (T2) relaxation of protons and result in greater contrast enhancement. As iron has the highest saturation magnetization at room temperature among all elements, and is biocompatible, it is an ideal candidate for MRI contrast enhancement. Nevertheless, the development of using iron NPs for magnetic applications has been challenging and limited compared to those of its oxides, due to the difficulty in preparing stable iron NPs with simple synthesis methods and precursors. 6] Under ambient conditions, iron NPs of 8 nm or smaller oxidize completely upon exposure to air. For larger NPs, an oxide shell of 3–4 nm forms instantly on the surface, forming iron/iron oxide core/shell NPs. Groundbreaking studies for the synthesis of iron NPs of larger than 8 nm has largely been achieved by decomposition of iron pentacarbonyl, [Fe(CO)5]. [6,8] Additional reports include the use of other precursors in forming iron nanocubes. However, all of these processes are limited in terms of ease of synthesis and scalability; [Fe(CO)5] is volatile and highly toxic, [5] and other processes involve precursors that are expensive and airsensitive, or require high decomposition temperatures. Here, we chose an easy to handle iron organometallic sandwich compound as the precursor and prepared singlecrystal iron NPs using a simple, low-temperature synthesis method. The iron nanocrystals oxidized naturally to form highly crystalline iron/iron oxide core/shell NPs. The ease of this synthesis facilitates the larger-scale application of stabilized iron NPs. To enable the use of these NPs in biological applications, the NP surface was modified to make the NPs water soluble. The strongly magnetic core/shell NPs are shown to be more effective T2 contrast agents for in vivo MRI and small tumor detection, compared to pure iron oxides. The successful detection of small tumors in vivo demonstrated here holds a great promise for accurate detection of early metastases in human lymph nodes, which has a large impact on the treatment and prognosis of a range of cancers. The iron/iron oxide core/shell NPs were prepared by first synthesizing iron nanocrystals by decomposition of the iron precursor [Fe(C5H5)(C6H7)], in the presence of oleylamine (OLA) stabilizing molecules. The non-carbonyl, sandwich compound was chosen for its simple preparation and ease of decomposition compared to other more stable sandwich compounds such as ferrocene. The synthesis was carried out in a closed reaction vessel under a mild hydrogen atmosphere, at 130 8C. The temperature required was lower than the usual temperature range (150–300 8C) needed for decomposition of other iron precursors in previous studies. Once [*] Dr. K. W. Feindel, Prof. P. T. Callaghan, Prof. R. D. Tilley School of Chemical and Physical Sciences and The MacDiarmid Institute for Advanced Materials and Nanotechnology, Victoria University of Wellington, Wellington 6012 (New Zealand) Fax: (+ 64)4-463-5237 E-mail: richard.tilley@vuw.ac.nz Dr. S. Cheong, Dr. B. Ingham Industrial Research Limited and The MacDiarmid Institute for Advanced Materials and Nanotechnology P. O. Box 31-310, Lower Hutt 5040 (New Zealand) Dr. P. Ferguson, Dr. I. F. Hermans Malaghan Institute of Medical Research P. O. Box 7060, Wellington 6012 (New Zealand)

Stabilizer-free poly(lactide-co-glycolide) nanoparticles for multimodal biomedical probes.

Apart from the reported PLGA submicro- and microspheres with broad size distribution, we have successfully developed a methodology using nanoprecipitation to prepare different sizes of PLGA nanoparticles with narrow size distributions. The newly developed PLGA nanoparticles could be readily modified with hydrophilic biomaterials on their surface and entrap hydrophobic drugs into their interiors. The encapsulation of FITC inside PLGA nanoparticles displayed a controlled release of drug system. The surfaces of the FITC entrapped PLGA nanoparticles were conjugated with quantum dots to serve as bimodal imaging probes. For nuclear transport, combination of nuclear localization signal (NLS) and PLGA nanoparticles, PLGA nanoparticles could successfully enter into HeLa cells nuclei. From tissue uptake results, PLGA nanoparticles had more uptaken by brain and liver than other tissues. The iron oxide nanoparticles-conjugated PLGA nanoparticle showed high efficiency of relaxivities r2 and could be used as the powerful magnetic resonance imaging (MRI) agents.

Comparative efficiencies of photothermal destruction of malignant cells using antibody-coated silica@Au nanoshells, hollow Au/Ag nanospheres and Au nanorods.

Three Au-based nanomaterials (silica@Au nanoshells, hollow Au/Ag nanospheres and Au nanorods) were evaluated for their comparative photothermal efficiencies at killing three types of malignant cells (A549 lung cancer cells, HeLa cervix cancer cells and TCC bladder cancer cells) using a CW NIR laser. Photodestructive efficiency was evaluated as a function of the number of nanoparticles required to destroy the cancer cells under 808 nm laser wavelength at fixed laser power. Of the three nanomaterials, silica@Au nanoshells needed the minimum number of particles to produce effective photodestruction, whereas Au nanorods needed the largest number of particles. Together with the calculated photothermal conversion efficiency, the photothermal efficiency rankings are silica@Au nanoshells > hollow Au/Ag nanospheres > Au nanorods. Additionally, we found that HeLa cells seem to present better heat tolerance than the other two cancer cell lines.

Multifunctional polymeric nanoparticles for combined chemotherapeutic and near-infrared photothermal cancer therapy in vitro and in vivo

Multifunctional Taxol-loaded PLGA nanoparticles show chemotherapeutic and photothermal destruction of cancer cells in vitro and in vivo.

Enhancing transversal relaxation for magnetite nanoparticles in mr imaging using Gd3+-chelated mesoporous silica shells

A new magnetic nanoparticle was synthesized in the form of Gd(3+)-chelated Fe(3)O(4)@SiO(2). The Fe(3)O(4) nanoparticle was octahedron-structured, was highly magnetic (∼94 emu/g), and was the core of an encapsulating mesoporous silica shell. DOTA-NHS molecules were anchored to the interior channels of the porous silica to chelate Gd(3+) ions. Because there were Gd(3+) ions within the silica shell, the transverse relaxivity increased 7-fold from 97 s(-1) mM(-1) of Fe(3)O(4) to 681 s(-1) mM(-1) of Gd(3+)-chelated Fe(3)O(4)@SiO(2) nanoparticles with r(2)/r(1) = 486. The large transversal relaxivity of the Gd(3+)-chelated Fe(3)O(4)@SiO(2) nanoparticles had an effective magnetic resonance imaging effect and clearly imaged lymph nodes. Physiological studies of liver, spleen, kidney, and lung tissue in mice infused with these new nanoparticles showed no damage and no cytotoxicity in Kupffer cells, which indicated that Gd(3+)-chelated Fe(3)O(4)@SiO(2) nanoparticles are biocompatible.

PLGA nanoparticles codeliver paclitaxel and Stat3 siRNA to overcome cellular resistance in lung cancer cells

Background: Effective cancer chemotherapy remains an important issue in cancer treatment, and signal transducer and activator of transcription-3 (Stat3) activation leads to cellular resistance of anticancer agents. Polymers are ideal vectors to carry both chemotherapeutics and small interfering ribonucleic acid (siRNA) to enhance antitumor efficacy. In this paper, poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with paclitaxel and Stat3 siRNA were successfully synthesized, and their applications in cancer cells were investigated. Methods: Firstly, paclitaxel was enclosed by PLGA nanoparticles through solvent evaporation. They were then coated with cationic polyethylenimine polymer (PLGA-PEI-TAX), enabling it to carry Stat3 siRNA on its surface through electrostatic interactions (PLGA-PEI-TAX-S3SI). The size, zeta potential, deliver efficacy, and release profile of the PLGA nanocomplexes were characterized in vitro. The cellular uptake, intracellular nanoparticle trajectory, and subsequent cellular events were evaluated after treatment with various PLGA nanocomplexes in human lung cancer A549 cells and A549-derived paclitaxel-resistant A549/T12 cell lines with α-tubulin mutation. Results: A549 and A549/T12 cells contain constitutively activated Stat3, and silencing Stat3 by siRNA made both cancer cells more sensitive to paclitaxel. Therefore, PLGA-PEI-TAX-S3SI was synthesized to test its therapeutic role in A549 and A549/T12 cells. Transmission electron microscopy showed the size of PLGA-PEI-TAX-S3SI to be around 250 nm. PLGA-PEI nanoparticles were nontoxic. PLGA-PEI-TAX was taken up by A549 and A549/T12 cells more than free paclitaxel, and they induced more condensed microtubule bundles and had higher cytotoxicity in these cancer cells. Moreover, the yellowish fluorescence observed in the cytoplasm of the cancer cells indicates that the PLGA-PEI nanoparticles were still simultaneously delivering Oregon Green paclitaxel and cyanine-5-labeled Stat3 siRNA 3 hours after treatment. Furthermore, after the cancer cells were incubated with the synthesized PLGA nanocomplexes, PLGA-PEI-TAX-S3SI suppressed Stat3 expression and induced more cellular apoptosis in A549 and A549/T12 cells compared with PLGA-PEI-TAX. Conclusion: The PLGA-PEI-TAX-S3SI complex provides a new therapeutic strategy to control cancer cell growth.

Functionalized nanoparticles provide early cardioprotection after acute myocardial infarction.

Recent developments in nanotechnology have created considerable potential toward diagnosis and cancer therapy. In contrast, the use of nanotechnology in tissue repair or regeneration remains largely unexplored. We hypothesized that intramyocardial injection of insulin-like growth factor (IGF)-1-complexed poly(D,L-lactide-co-glycolide) (PLGA) nanoparticles (PLGA-IGF-1 NPs) increases IGF-1 retention, induces Akt phosphorylation, and provides early cardioprotection after acute myocardial infarction (MI). We synthesized 3 different sizes of PLGA particles (60 nm, 200 nm, and 1 μm) which were complexed with IGF-1 using electrostatic force to preserve the biological function of IGF-1. Afterward, we injected PLGA-IGF-1 NPs in the heart after MI directly. Compared with the other two larger particles, the 60 nm-sized PLGA-IGF-1 NPs carried more IGF-1 and induced more Akt phosphorylation in cultured cardiomyocytes. PLGA-IGF-1 NPs also prolonged Akt activation in cardiomyocytes up to 24h and prevented cardiomyocyte apoptosis induced by doxorubicin in a dose-dependent manner. In vivo, PLGA-IGF-1 NP treatment significantly retained more IGF-1 in the myocardium than the IGF-1 alone treatment at 2, 6, 8, and 24 h. Akt phosphorylation was detected in cardiomyocytes 24h post-MI only in hearts receiving PLGA-IGF-1 NP treatment, but not in hearts receiving injection of PBS, IGF-1 or PLGA NPs. Importantly, a single intramyocardial injection of PLGA-IGF-1 NPs was sufficient to prevent cardiomyocyte apoptosis (P<0.001), reduce infarct size (P<0.05), and improve left ventricle ejection fraction (P<0.01) 21 days after experimental MI in mice. Our results not only demonstrate the potential of nanoparticle-based technology as a new approach to treating MI, but also have significant implications for translation of this technology into clinical therapy for ischemic cardiovascular diseases.