This study adapted AuroLase® Therapy, previously reported for the treatment of brain tumors, to the treatment of
prostate disease by 1) using normal canine prostate in vivo, directly injected with a solution of nanoparticles as a
proxy for prostate tumor and, 2) developing an appropriate laser dosimetry for prostate which is which is subablative
in native prostate while simultaneously producing photothermal coagulation in prostate tissue containing
Healthy, mixed-breed hound dogs were given surgical laparotomies during which nanoshells were injected directly
into one or both prostate hemispheres. Laser energy was delivered percutaneously to the parenchyma of the prostate
along 1-5 longitudinal tracts via a liquid-cooled optical fiber catheter terminated with a 1-cm isotropic diffuser after
which the incision was closed and sutured using standard surgical techniques. The photothermal lesions were
permitted to resolve for up to 8 days, after which each animal was euthanized, necropsied, and the prostate taken for
We developed a laser dosimetry which is sub- to marginally ablative in native prostate and simultaneously ablative
of prostate tissue containing nanoshells which would indicate a viable means of treating tumors of the prostate
which are known from other studies to accumulate nanoshells. Secondly, we determined that multiple laser
treatments of nanoshell-containing prostate tissue could be accomplished while sparing the urethra and prostate
capsule thermal damage. Finally, we determined that the extent of damage zone radii correlate positively with
nanoshell concentration, and negatively to the length of time between nanoshell injection and laser treatment.
The photothermal ablation of solid tumors using exogenous, near-infrared (NIR)-absorbing nanoparticles has been previously investigated using various preclinical models and is currently being evaluated in the clinic. Here, we evaluate the circulation kinetics, preliminary toxicity, and efficacy of photothermal ablation of solid tumors using gold nanorods systemically delivered and passively accumulated in a murine subcutaneous colon cancer model. Tumored animals were infused with nanorods followed by the percutaneous illumination of the tumor with an 808-nm laser. Control groups consisted of laser-only, nanorod-only, and untreated tumored animals. The survival of the treated and control groups were monitored for 60 days post-treatment. The survival of the photothermally treated group was statistically longer than the control groups, with approximately 44% tumor free through the evaluation period. Histopathology of the major organs of animals infused with nanorods did not indicate any significant toxicity at 60 days post-treatment. Particle biodistribution was evaluated by elemental analysis of the major organs of untumored mice at 1, 7, and 30 days after infusion with nanorods. Elemental analysis indicates nanorod clearance from the blood and retention by the reticuloendothelial system. This study indicates that gold nanorods are promising agents for photothermal ablation of solid tumors.
Gold nanoshells (GNS) are a new class of nanoparticles that can be optically tuned to scatter or absorb light from the near-ultraviolet to near-infrared (NIR) region by varying the core (dielectric silica)/shell (gold) ratio. In addition to spectral tunability, GNS are inert and bioconjugatable, making them potential labels for in vivo imaging and therapy of tumors. We report the use of GNS as exogenous contrast agents for enhanced visualization of tumors using narrow-band imaging (NBI). NBI takes advantage of the strong NIR absorption of GNS to distinguish between blood and nanoshells in the tumor by imaging in narrow wavelength bands in the visible and NIR, respectively. Using tissue-simulating phantoms, we determined the optimum wavelengths to enhance contrast between blood and GNS. We then used the optimum wavelengths for ex vivo imaging of tumors extracted from human colon cancer xenograft bearing mice injected with GNS. Systemically delivered GNS accumulated passively in tumor xenografts by the enhanced permeability and retention (EPR) effect. Ex vivo NBI of tumor xenografts demonstrated heterogeneous distribution of GNS with a clear distinction from the tumor vasculature. The results of this study demonstrate the feasibility of using GNS as contrast agents to visualize tumors using NBI.
Gold nanoshells (GNS) are a new class of nanoparticles that can be optically tuned to scatter or absorb light from the
near-ultraviolet to near-infrared (NIR) region by varying the core (dielectric silica) /shell (gold) ratio. In addition to
spectral tunability, GNS are inert and bioconjugatable making them potential labels for in vivo imaging and therapy of
tumors. We report the use of GNS as exogenous contrast agents for enhanced visualization of tumors using narrow band
imaging (NBI). NBI takes advantage of the strong NIR absorption of GNS to distinguish between blood and nanoshells
in the tumor by imaging in narrow wavelength bands in the visible and NIR, respectively. Using tissue-simulating
phantoms, we determined the optimum wavelengths to enhance contrast between blood and GNS. We then used the
optimum wavelengths for ex-vivo imaging of tumors extracted from human colon cancer xenograft bearing mice injected
with GNS. Systemically delivered GNS accumulated passively in tumor xenografts by the enhanced permeability and
retention (EPR) effect. Ex-vivo NBI of tumor xenografts demonstrated tumor specific heterogeneous distribution of GNS
with a clear distinction from the tumor vasculature. The results of this study demonstrate the feasibility of using GNS as
contrast agents to visualize tumors using NBI.
We report on a pilot study demonstrating a proof of concept for the passive delivery of nanoshells to an orthotopic tumor
where they induce a local, confined therapeutic response distinct from that of normal brain resulting in the photo-thermal
ablation of canine Transmissible Venereal Tumor (cTVT) in a canine brain model. cTVT fragments grown in SCID
mice were successfully inoculated in the parietal lobe of immuno-suppressed, mixed-breed hound dogs. A single dose of
near-infrared absorbing, 150 nm nanoshells was infused intravenously and allowed time to passively accumulate in the
intracranial tumors which served as a proxy for an orthotopic brain metastasis. The nanoshells accumulated within the
intracranial cTVT suggesting that its neo-vasculature represented an interruption of the normal blood-brain barrier.
Tumors were thermally ablated by percutaneous, optical fiber-delivered, near-infrared radiation using a 3.5 W average,
3-minute laser dose at 808 nm that selectively elevated the temperature of tumor tissue to 65.8±4.1ºC. Identical laser
doses applied to normal white and gray matter on the contralateral side of the brain yielded sub-lethal temperatures of
48.6±1.1ºC. The laser dose was designed to minimize thermal damage to normal brain tissue in the absence of
nanoshells and compensate for variability in the accumulation of nanoshells in tumor. Post-mortem histopathology of
treated brain sections demonstrated the effectiveness and selectivity of the nanoshell-assisted thermal ablation.
As the use of lasers proliferate in military and civilian applications, the importance of laser eye protection becomes increasingly significant. Of particular relevance is protection from non-visible laser sources operating in the near-infrared, as it is impossible to determine when the eye is being exposed to such harmful radiation. Current technologies for laser eye protection, such as dyes or reflective coatings of visors/glasses, are generally bulky, which presents a challenge for use and integration with oxygen masks, helmets and night vision apparatus. A contact-lens based laser eye protection system would offer the advantage of minimal modification of current equipment to provide protection against laser exposure.
A laser eye protection system has been developed based on the unique optical properties of gold nanoshells. Gold nanoshells consist of a dielectric silica core, surrounded by a thin (nm) shell of gold. By adjusting the core size and the shell thickness, these nanoparticles can provide high extinction levels throughout the near-infrared region of the spectrum. Unlike some organic dyes, the particles are photostable and non-toxic, increasing the practical life of the lens. The design and fabrication of a soft contact lens containing nanoshells is described. The optical and physiochemical properties are compared to a standard soft contact control. The results of preliminary toxicity studies are also presented
Given their tunable optical properties and high optical absorption and scattering cross sections, gold nanoshells (GNS) have been explored for a number of in vitro and in vivo imaging contrast and cancer therapy agents. While it has been shown that GNSs preferentially accumulate at the tumor site, little is known about the accumulation kinetics within the tumor. We demonstrate accumulation kinetics of GNSs in bulk tumors and histology slides using two-photon induced photoluminescence (TPIP) imaging. We found that GNSs had a heterogeneous distribution with higher accumulation at the tumor cortex. In addition, GNSs were observed in unique patterns surrounding the perivascular region. These results demonstrate that direct luminescence based imaging of metal nanoparticles provides high resolution and molecular specific multiplexed images.
The use of near-infrared absorbing nanoparticles recently has been proposed for the minimally invasive photothermal
ablation of solid tumors, and this approach currently is being investigated in the clinic. One class of nanoparticles, gold
nanorods, has been investigated for the ablation of various cancer types using both direct injection and systemic delivery.
Here we investigate the photothermal ablation of colon cancer in an animal model using intravenously delivered gold
nanorods. Nanorods with an aspect ratio of ~3.2 and an extinction peak of 774 nm were PEGylated, suspended in an
isotonic solution, and infused into the tail vein of BALB/c mice bearing subcutaneous CT26.wt murine colon cancer
tumors. After 24 hrs, an isotropic laser fiber was inserted through a small incision in the skin to a point proximate to and
beneath the tumor. The area was illuminated with 3.5 W average power for 3 minutes. Control groups consisted of
laser-only, nanorod-only and untreated tumored animals. The survival of the animals receiving nanorod-based
photothermal ablation was statistically longer than the control groups with >44% complete response. This work
demonstrates the promise of systemically delivering nanoparticles to tumors for thermal ablation
Gold nanoshells are a novel class of hybrid metal nanoparticles whose unique optical properties have spawned new
applications including more sensitive molecular assays and cancer therapy. We report a new photo-physical property of
nanoshells (NS) whereby these particles glow brightly when excited by near-infrared light. Specifically, we demonstrate
NS excited at 780 nm produce strong two-photon induced photoluminescence (TPIP). We characterized the
luminescence brightness of NS, comparing to that of fluorescein-labeled fluorescent beads (FB). We find that NS are 140
times brighter than FB. To demonstrate the potential application of this bright TPIP signal for biological imaging, we
imaged the 3D distribution of gold nanoshells targeted to murine tumors.