Yasuyuki Akiyama

The effects of PEG grafting level and injection dose on gold nanorod biodistribution in the tumor-bearing mice

Gold nanorods have strong absorbance in the near infrared region, which penetrates deeply into tissues, where the absorbed light energy is converted into heat. Therefore, gold nanorods are expected to act as an effective contrast agent for in vivo bioimaging and as a thermal converter for photothermal therapy. We grafted various amounts of polyethylene glycol (PEG) onto the surface of gold nanorods and investigated the effects of grafting level and injection dose on the biodistribution in the tumor-bearing mice after intravenous injection and enhanced permeability and retention (EPR). Higher PEG grafting levels were advantageous for reticuloendothelial system (RES) avoidance and for suppression of aggregation of the gold nanorods in the circulation. Modification with a PEG:gold molar ratio of 1.5 was sufficient to show both prolonged circulation and the EPR effect. When the injection dose was increased above 19.5 microg of gold, the RES uptake in the liver was saturated and surplus gold nanorods were distributed to other tissues, especially the spleen and the tumor. The results of this study will provide an important basis for the development of cancer therapies mediated by the photothermal effect of gold nanorods.

Poly(ethylene glycol)-Modified Gold Nanorods as a Photothermal Nanodevice for Hyperthermia

Gold nanorods, which have a strong surface plasmon band at the near-infrared region, absorb light energy which is then converted to heat. Since near-infrared light can penetrate deeply into tissue, gold nanorods are expected to be useful as photosensitizers for photothermal therapy. In this study, the length of the poly(ethylene glycol) (PEG) chain was optimized in order to stabilize the gold nanorods in the blood circulation after intravenous injection. PEG5000- and PEG10000-modified gold nanorods showed higher stability in the blood circulation compared with PEG2000- and PEG20000-modified gold nanorods. As a demonstration of photothermal tissue damage, PEG5000-modified gold nanorods were injected into the muscle in the hind limbs of a mouse, and then irradiated with near-infrared pulsed laser light. Significant tissue damage was observed only in the presence of gold nanorods and laser irradiation. We next injected the gold nanorods directly into subcutaneous tumors in mice, and then irradiated the tumor with near-infrared pulsed laser light. Significant suppression of tumor growth was observed. In the case of the intravenous injection of gold nanorods, the suppression of tumor growth was weaker than for the case of direct injection, indicating that the targeted delivery of gold nanorods to the tumor tissue is an important key to improve the therapeutic effect.

Characterization of silver ions adsorbed on gold nanorods: surface analysis by using surface-assisted laser desorption/ionization time-of-flight mass spectrometry

Surface-assisted laser desorption/ionization time-of-flight mass spectrometry (SALDI-MS) indicated AgBr2-, which adsorbed on gold nanorod surfaces, was a key material to control the anisotropic growth of gold nanorods.

In vivo monitoring of intravenously injected gold nanorods using near-infrared light

Gold nanorods showing surface plasmon (SP) bands in the near-IR region are used as bioimaging probes that respond to near-IR light in mice. The SP bands of intravenously injected polyethylene glycol-modified gold nanorods are directly monitored from the mouse abdomen by using a spectrophotometer equipped with an integrating sphere. The absorbance at 900 nm from the gold nanorods immediately increases after injection and reaches a plateau. The injection of phosphatidylcholine-modified gold nanorods also increases the absorbance at 900 nm, but the absorbance decreases single exponentially with a 1.3-min half-life. In vivo spectral changes of gold nanorods depend on the surface characteristics, and can be observed in real time using simple spectroscopic measurements.

Controlled release of PEG chain from gold nanorods: Targeted delivery to tumor

Gold nanorods exhibit strong absorbance of light in the near infrared region, which penetrates deeply into tissues. Since the absorbed light energy is converted into heat, gold nanorods are expected to act as a contrast agent for in vivo bioimaging and as a thermal converter for photothermal therapy. To construct a gold nanorod targeted delivery system for tumor a peptide substrate for urokinase-type plasminogen activator (uPA), expressed specifically on malignant tumors, was inserted between the PEG chain and the surface of the gold nanorods. In other words, we constructed PEG-peptide-modified gold nanorods. After mixing the gold nanorods with uPA, the PEG chain was released from the surface of the gold and subsequently nanorod aggregation took place. The formation of the aggregation was monitored as a decrease in light absorption at 900 nm. Tumor homogenate induced a significant decrease in this absorption. Larger amount of the PEG-peptide-modified gold nanorods bound to cells expressing uPA in vitro compared with control gold nanorods, which had scrambled sequence of the peptide. The PEG-peptide-modified gold nanorods showed higher accumulation in tumor than the control after they were injected intravenously into tumor-bearing mice, however, the density of the peptide on the surface of the gold nanorods was a key factor of their biodistributions. This targeted delivery system, which responds to uPA activity, is expected to be a powerful tool for tumor bioimaging and photothermal tumor therapy.

Active accumulation of gold nanorods in tumor in response to near-infrared laser irradiation

Gold nanorods, rod-shaped gold nanoparticles, have strong absorbance in the near-infrared region, and the absorbed light energy can be converted to heat, the so-called photothermal effect. The gold nanorods were coated with thermoresponsive polymers, which have different phase transition temperatures that were controlled by adding comonomers, N,N-dimethylacrylamide (DMAA) or acrylamide (AAm) to N-isopropylacrylamide (NIPAM). The phase transition temperatures of poly(NIPAM-DMAA) and poly(NIPAM-AAm)-coated gold nanorods were 38 and 41 °C, respectively, while polyNIPAM-coated gold nanorods showed phase transition at 34 °C. Irradiation of the coated gold nanorods using the near-infrared laser induced a decrease in their sizes due to a phase transition of the polymer layers. Poly(NIPAM-AAm)-coated gold nanorods stably circulated in the blood flow without a phase transition after intravenous injection. Irradiation of near-infrared light at a tumor after the injection resulted in the gold specifically accumulating in the tumor. This novel accumulation technique which combines a thermoresponsive polymer and the photothermal effect of the gold nanorods should be a powerful tool for targeted delivery in response to light irradiation.

Conversion of rod-shaped gold nanoparticles to spherical forms and their effect on biodistribution in tumor-bearing mice.

Gold nanorods that have an absorption band in the near-infrared region and a photothermal effect have been used as nanodevices for near-infrared imaging and thermal therapy. Choice of the optimal shape of gold nanorods which relates optical properties and in vivo biodistribution is important for their applications. In the present study, to investigate the relationship between the shape of gold nanorods and their biodistribution after intravenous injection, we first prepared two types of gold nanorods that had distinct aspect ratios but had the same volume, zeta potential, and PEG density on the gold surface. Biodistributions of the two types of gold nanorods after intravenous injection into tumor-bearing mice were then compared. Although a slight difference in accumulation in the spleen was observed, no significant difference was observed in the liver, lung, kidney, and tumors. These results suggest that biodistribution of the gold nanorods in the aspect ratio range of 1.7 to 5.0, diameter of 10 to 50 nm, and volume of approximately 4 × 103 nm3 was dependent mainly on surface characteristics, PEG density, and zeta potential.

PEG-silica-modified gold nanorods that retain their optical properties in tumor tissues

Gold nanorods modified with polyethylene glycol (PEG) chains via Au–S bonds form aggregates, and their absorption spectra broaden in tumor tissues. In contrast, the gold nanorods modified here via the crosslinking of PEG chains on the silica shell on gold nanorods showed enhanced permeability and retention effects and retained the optical properties of the original gold nanorods in tumor tissues.

In vivo monitoring of gold nanorods and tissue damage mediated with their photothermal effect

Gold nanorods have a strong surface plasmon band at the near infrared region. The absorbed light energy is then converted to heat. Since near infrared light can penetrate deeply into tissue, gold nanorods are expected to be used as a contrast agent for bioimaging using the near infrared light and photosensitizers for photothermal therapy. The surface plasmon bands of intravenously injected the gold nanorods were directly monitored from the mouse abdomen by using a spectrophotometer equipped with an integrating sphere. The absorbance at 900 nm from PEG5,000-modified gold nanorods immediately increased after injection and reached a plateau. The injection of phosphatidylcholine-modified gold nanorods also increased the absorbance at 900 nm, but the absorbance decreased single exponentially with a 1.3-min half-life. To demonstrate photothermal tumor therapy, the PEG-modified gold nanorods were directly injected into subcutaneous tumors in mice, then, near infrared laser light was irradiated to the tumor. After the treatment, significant suppression of tumor growth was observed.