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.
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
In this study, high resolution backward-mode photoacoustic microscopy (PAM) is used to noninvasively image progressive extravasation and accumulation of nanoshells within a solid tumor in vivo. PAM takes advantage of the strong near-infrared absorption of nanoshells and their extravasation tendency from leaky tumor vasculatures for imaging. Subcutaneous tumors are grown on immunocompetent BALB/c mice. Polyethylene glycol (PEGylated) nanoshells with a peak optical absorption at ~800 nm are intravenously administered. With an 800-nm laser source, a prescan prior to nanoshell injection is taken to determine the background that is free of nanoshell accumulation. After injection, the 3-D nanoshell distribution at the tumor foci is monitored by PAM for 6 h. Experimental results show that accumulated nanoshells delineate the tumor position. Nanoshell accumulation is heterogeneous in tumors: more concentrated within the tumor cortex and largely absent from the tumor core. Because nanoshells have been recently demonstrated to enhance thermal therapy of subcutaneous tumors, we anticipate that PAM will be an important aid before, during, and after nanoshell thermal therapy.
Cooled fiber tip technology has significantly improved the volume coverage of laser induced thermal therapy (LITT),
making LITT an attractive technology for the minimally invasive treatment of cancer. Gold coated nanoshells can be
tuned to experience a plasmon resonance at a desired laser frequency, there introduction into the treatment region can
greatly amplify the effectiveness of the thermal treatment. The goal is to conformaly heat the target, while sparing
surrounding healthy tissue. To this end a treatment option that is self-confining to the target lesion is highly desirable.
This can be achieved in the liver by allowing nanoshells to be taken up by the healthy tissue of the liver as part of their
natural removal from the blood stream. The lesion is then incased inside the nanoshell laden tissue of the surrounding
healthy tissue. When an interstitial laser probe is introduced into the center of the lesion the thermal radiation scatters
outward until it interacts with and is absorbed by the nanoshells located around the lesion periphery. As the periphery
heats it acts as secondary source of thermal radiation, sending heat back into lesion and giving rise to ablative
temperatures within the lesion while sparing the surrounding tissue.
In order to better monitor therapy and know when the target volume has been ablated, or exceeded, accurate knowledge
is needed of both the spatial distribution of heating and the maximum temperature achieved. Magnetic resonance
temperature imaging (MRTI) is capable of monitoring the spatiotemporal distribution of temperature in vivo.
Experiments have been performed in vitro using a dog liver containing nanoshells (concentration 860ppm) and a tissue
like lesion phantom designed to have the optical properties of liver metastasis .
Despite convincing evidence for hyperthermic radiosensitization, the invasive means of achieving and monitoring
hyperthermia and the lack of good thermal dosimetry have hindered its use in routine clinical practice. A non-invasive
method to generate and monitor hyperthermia would provide renewed enthusiasm for such treatments. Near-infrared
absorbing gold nanoshells have been shown to accumulate preferentially in tumors via the enhanced permeability and
retention effect and have been used for thermal ablation of tumors. We evaluated the use of these nanoshells to generate
hyperthermia to evaluate the anti-tumor effects of combining gold nanoshell mediated hyperthermia with radiotherapy.
Laser settings were optimized for hyperthermia in a mouse xenograft model to achieve a temperature rise of 40- 41°C in
the tumor periphery and 37-38°C (ΔT=4-5°C) deeper within the tumors. The ΔT measurements were verified using both
thermocouple and magnetic resonance thermal imaging (MRTI) temperature measurements. Tumor re-growth delay was
estimated by measuring tumor size after treatment with radiation (10Gy single dose), hyperthermia (15 minutes at 40°C),
and hyperthermia followed by radiation and control. Significant difference (p <0.05) in the tumor volume doubling time
was observed between the radiation group (13 days) and combination treatment group (25 days). The
immunofluorescence staining for the hypoxic, proliferating cells and the vasculature corroborated our hypothesis that the
radiosensitization is in part mediated by increased initial perfusion and subsequent collapse of vasculature that leads to
acute inflammatory response in the tumor. The increased vascular perfusion immediately after gold nanoshell mediated
hyperthermia is confirmed by dynamic contrast enhanced magnetic resonance imaging.
This study investigates the potential of using gold nanoshells to mediate a thermally induced modulation of tumor
vasculature in experimental prostate tumors. We demonstrate that after passive extravasation and retention of the
circulating nanoshells from the tumor vasculature into the tumor interstitium, the enhanced nanoshells absorption of
near-infrared irradiation over normal vasculature, can be used to increase tumor perfusion or shut it down at powers
which result in no observable affects on tissue without nanoshells. Temperature rise was monitored in real time using
magnetic resonance temperature imaging and registered with perfusion changes as extrapolated from MR dynamic
contrast enhanced (DCE) imaging results before and after each treatment. Results indicate that nanoshell mediated
heating can be used to improve perfusion and subsequently enhance drug delivery and radiation effects, or be used to
shut down perfusion to assist in thermal ablative therapy delivery.
In this study, high resolution reflection-mode (backward-mode) photoacoustic microscopy (PAM) is used to noninvasively image progressive extravasation and accumulation of nanoshells within a solid tumor in vivo. This study takes advantage of the strong near-infrared absorption of nanoshells, a novel type of optically tunable gold nanoparticles that tend to extravasate from leaky tumor vasculatures (i.e., passive targeting) via the "enhanced permeability and retention" effect due to their nanoscale size. Tumors were grown in immunocompetent BALB/c mice by subcutaneous inoculation of CT26.wt murine colon carcinoma cells. PEGylated nanoshells with a peak optical absorption at ~800 nm were intravenously administered. Pre-scans prior to nanoshell injection were taken using a 584-nm laser source to highlight blood content and an 800-nm laser source to mark the background limit for nanoshell accumulation. After injection, the three-dimensional nanoshell distribution inside the tumor was monitored by PAM for 7 hours. Experimental results show that nanoshell accumulation is heterogeneous in tumors: more concentrated within the tumor cortex and largely absent from the tumor core. This correlates with others' observation that drug delivery within tumor cores is ineffective because of both high interstitial pressure and tendency to necrosis of tumor cores. Since nanoshells have been recently applied to thermal therapy for subcutaneous tumors, we anticipate that PAM will be important to this therapeutic technique.
Laser induced thermal therapy is used in conjunction with gold coated silica core nanoshells and magneticresonance
temperature imaging (MRTI). The nanoshells are embedded in phantom or in vivo tumors and
heat preferentially compared to surrounding tissue when the laser is applied. The tissues thermal response
is varied by either the laser power or the nanoshell concentration. In this way precise control of the heating
can be achieved. This results in the ability to quantitatively monitor therapeutic temperature changes that
occur in a spatiotemporally controlled way. This provides an unprecedented means proscribing and
monitoring a treatment in real time and the ability to make precise corrections when necessary.