Roadmap for metal nanoparticles in radiation therapy: current status, translational challenges, and future directions.

This roadmap outlines the potential roles of metallic nanoparticles (MNPs) in the field of radiation therapy. MNPs made up of a wide range of materials (from Titanium, Z = 22, to Bismuth, Z = 83) and a similarly wide spectrum of potential clinical applications, including diagnostic, therapeutic (radiation dose enhancers, hyperthermia inducers, drug delivery vehicles, vaccine adjuvants, photosensitizers, enhancers of immunotherapy) and theranostic (combining both diagnostic and therapeutic), are being fabricated and evaluated. This roadmap covers contributions from experts in these topics summarizing their view of the current status and challenges, as well as expected advancements in technology to address these challenges.

Evaluation of the toxicity of intravenous delivery of auroshell particles (gold-silica nanoshells).

Gold nanoshells (155 nm in diameter with a coating of polyethylene glycol 5000) were evaluated for preclinical biocompatibility, toxicity, and biodistribution as part of a program to develop an injectable device for use in the photothermal ablation of tumors. The evaluation started with a complete good laboratory practice (GLP) compliant International Organization for Standardization (ISO)-10993 biocompatibility program, including cytotoxicity, pyrogenicity (US Pharmacopeia [USP] method in the rabbit), genotoxicity (bacterial mutagenicity, chromosomal aberration assay in Chinese hamster ovary cells, and in vivo mouse micronucleus), in vitro hemolysis, intracutaneous reactivity in the rabbit, sensitization (in the guinea pig maximization assay), and USP/ISO acute systemic toxicity in the mouse. There was no indication of toxicity in any of the studies. Subsequently, nanoshells were evaluated in vivo by intravenous (iv) infusion using a trehalose/water solution in a series of studies in mice, Sprague-Dawley rats, and Beagle dogs to assess toxicity for time durations of up to 404 days. Over the course of 14 GLP studies, the gold nanoshells were well tolerated and, when injected iv, no toxicities or bioincompatibilities were identified.

Selective nanoparticle-directed ablation of the canine prostate.

BACKGROUND AND OBJECTIVES: Prostate cancer is the most frequent cancer type and the second most common cause of cancer death among US men. This study, adapted a previously reported nanoparticle-directed photothermal treatment of brain tumors to the treatment of prostate disease by using normal canine prostate in vivo, directly injected with a suspension of nanoparticles as a proxy for prostate tumor, and by developing laser dosimetry for prostate which is marginally ablative in native tissue, yet producing photothermal coagulation in prostate tissue containing nanoparticles. METHODS: Canine prostates were exposed by surgical laparotomy and directly injected with suspensions of nanoparticles (nanoshells) and irradiated by a NIR laser source delivered percutaneously by an optical fiber catheter and isotropic diffuser. The photothermal lesions were permitted to resolve for up to 8 days, at which time each animal was euthanized, necropsied, and the prostate taken for histopathological and elemental analysis. RESULTS: Nanoparticles were retained for up to 4 hours in prostate and served as a proxy for prostate tumor. A marginally ablative laser dose of 3.0 W for 3 minutes was developed which would yield 4 mm-radius coagulo-necrotic lesions if nanoparticles were present. CONCLUSION: We have shown that the addition of nanoshells to native tissue, combined with a marginally ablative laser dose can generate ablative thermal lesions, and that the radial extent of the thermal lesions is strictly confined to within ∼4 mm of the optical fiber with sub-millimeter uncertainty. This, in turn, suggests a means of precise tumor ablation with an ability to obviate damage to critical structures limited primarily by the precision with which the optical fiber applicator can be placed. In so doing, it should be possible to realize a precise, nerve bundle and urethra sparing prostate cancer treatment using a minimally invasive, percutaneous approach.

Photothermal therapy in a murine colon cancer model using near-infrared absorbing gold nanorods.

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.

Near-infrared narrow-band imaging of gold/silica nanoshells in 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.

Feasibility study of particle-assisted laser ablation of brain tumors in orthotopic canine model.

We report on a pilot study showing 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 photothermal ablation of canine transmissible venereal tumor (cTVT) in a canine brain model. cTVT fragments grown in severe combined immunodeficient mice were successfully inoculated in the parietal lobe of immunosuppressed, mixed-breed hound dogs. A single dose of near-IR (NIR)-absorbing, 150-nm nanoshells was infused i.v. 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 neovasculature represented an interruption of the normal blood-brain barrier. Tumors were thermally ablated by percutaneous, optical fiber-delivered, NIR 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 +/- 4.1 degrees C. Identical laser doses applied to normal white and gray matter on the contralateral side of the brain yielded sublethal temperatures of 48.6 +/- 1.1 degrees C. 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. Postmortem histopathology of treated brain sections showed the effectiveness and selectivity of the nanoshell-assisted thermal ablation.

In Vivo Detection of Gold Nanoshells in Tumors Using Diffuse Optical Spectroscopy.

This study demonstrates the use of diffuse optical spectroscopy (DOS) for the noninvasive measurement of gold nanoshell concentrations in tumors of live mice. We measured the diffuse optical spectra (500-800 nm) using an optical fiber probe placed in contact with the tissue surface. We performed in vitro studies on tissue phantoms illustrating an accurate measurement of gold-silica nanoshell concentration within 12.6% of the known concentration. In vivo studies were performed on a mouse xenograft tumor model. DOS spectra were measured at preinjection, immediately postinjection, 1 and 24 h postinjection times, and the nanoshell concentrations were verified using neutron activation analysis.

Photo-thermal tumor ablation in mice using near infrared-absorbing nanoparticles.

The following study examines the feasibility of nanoshell-assisted photo-thermal therapy (NAPT). This technique takes advantage of the strong near infrared (NIR) absorption of nanoshells, a new class of gold nanoparticles with tunable optical absorptivities that can undergo passive extravasation from the abnormal tumor vasculature due to their nanoscale size. Tumors were grown in immune-competent mice by subcutaneous injection of murine colon carcinoma cells (CT26.WT). Polyethylene glycol (PEG) coated nanoshells (approximately 130 nm diameter) with peak optical absorption in the NIR were intravenously injected and allowed to circulate for 6 h. Tumors were then illuminated with a diode laser (808 nm, 4 W/cm2, 3 min). All such treated tumors abated and treated mice appeared healthy and tumor free >90 days later. Control animals and additional sham-treatment animals (laser treatment without nanoshell injection) were euthanized when tumors grew to a predetermined size, which occurred 6-19 days post-treatment. This simple, non-invasive procedure shows great promise as a technique for selective photo-thermal tumor ablation.