L. R. Hirsch

Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance

Metal nanoshells are a class of nanoparticles with tunable optical resonances. In this article, an application of this technology to thermal ablative therapy for cancer is described. By tuning the nanoshells to strongly absorb light in the near infrared, where optical transmission through tissue is optimal, a distribution of nanoshells at depth in tissue can be used to deliver a therapeutic dose of heat by using moderately low exposures of extracorporeally applied near-infrared (NIR) light. Human breast carcinoma cells incubated with nanoshells in vitro were found to have undergone photothermally induced morbidity on exposure to NIR light (820 nm, 35 W/cm2), as determined by using a fluorescent viability stain. Cells without nanoshells displayed no loss in viability after the same periods and conditions of NIR illumination. Likewise, in vivo studies under magnetic resonance guidance revealed that exposure to low doses of NIR light (820 nm, 4 W/cm2) in solid tumors treated with metal nanoshells reached average maximum temperatures capable of inducing irreversible tissue damage (ΔT = 37.4 ± 6.6°C) within 4-6 min. Controls treated without nanoshells demonstrated significantly lower average temperatures on exposure to NIR light (ΔT < 10°C). These findings demonstrated good correlation with histological findings. Tissues heated above the thermal damage threshold displayed coagulation, cell shrinkage, and loss of nuclear staining, which are indicators of irreversible thermal damage. Control tissues appeared undamaged.

Nanoshell-Enabled Photonics-Based Imaging and Therapy of Cancer

Metal nanoshells are a novel type of composite spherical nanoparticle consisting of a dielectric core covered by a thin metallic shell which is typically gold. Nanoshells possess highly favorable optical and chemical properties for biomedical imaging and therapeutic applications. By varying the relative the dimensions of the core and the shell, the optical resonance of these nanoparticles can be precisely and systematically varied over a broad region ranging from the near-UV to the mid-infrared. This range includes the near-infrared (NIR) wavelength region where tissue transmissivity peaks. In addition to spectral tunability, nanoshells offer other advantages over conventional organic dyes including improved optical properties and reduced susceptibility to chemical/thermal denaturation. Furthermore, the same conjugation protocols used to bind biomolecules to gold colloid are easily modified for nanoshells. In this article, we first review the synthesis of gold nanoshells and illustrate how the core/shell ratio and overall size of a nanoshell influences its scattering and absorption properties. We then describe several examples of nanoshell-based diagnostic and therapeutic approaches including the development of nanoshell bioconjugates for molecular imaging, the use of scattering nanoshells as contrast agents for optical coherence tomography (OCT), and the use of absorbing nanoshells in NIR thermal therapy of tumors.

CONTROLLING THE SURFACE ENHANCED RAMAN EFFECT VIA THE NANOSHELL GEOMETRY

Systematic variation of the internal geometry of a dielectric core-metal shell nanoparticle allows the local electromagnetic field at the nanoparticle surface to be precisely controlled. The strength of the field as a function of core and shell dimension is measured by monitoring the surface enhanced Raman scattering (SERS) response of nonresonant molecular adsorbates (para-mercaptoaniline) bound to the nanoparticle surface. The SERS enhancement appears to be directly and exclusively due to nanoparticle geometry. Effective SERS enhancements of 106 are observable in aqueous solution, which correspond to absolute enhancements of 1012 when reabsorption of Raman emission by nearby nanoparticles is taken into account.Systematic variation of the internal geometry of a dielectric core-metal shell nanoparticle allows the local electromagnetic field at the nanoparticle surface to be precisely controlled. The strength of the field as a function of core and shell dimension is measured by monitoring the surface enhanced Raman scattering (SERS) response of nonresonant molecular adsorbates (para-mercaptoaniline) bound to the nanoparticle surface. The SERS enhancement appears to be directly and exclusively due to nanoparticle geometry. Effective SERS enhancements of 106 are observable in aqueous solution, which correspond to absolute enhancements of 1012 when reabsorption of Raman emission by nearby nanoparticles is taken into account.

Gold nanoshell bioconjugates for molecular imaging in living cells

Advances in scattering-based optical imaging technologies offer a new approach to noninvasive point-of-care detection, diagnosis, and monitoring of cancer. Emerging photonics technologies provide a cost-effective means to image tissue in vivo with high resolution in real time. Advancing the clinical potential of these imaging strategies requires the development of optical contrast agents targeted to specific molecular signatures of disease. We describe the use of a novel class of contrast agents based on nanoshell bioconjugates for molecular imaging in living cells. Nanoshells offer significant advantages over conventional imaging probes including continuous and broad wavelength tunability, far greater scattering and absorption coefficients, increased chemical stability, and improved biocompatibility. We show that nanoshell bioconjugates can be used to effectively target and image human epidermal growth factor receptor 2 (HER2), a clinically relevant biomarker, in live human breast carcinoma cells.

Nanoshell-mediated near infrared photothermal tumor therapy

A novel photothermal therapy of neoplastic tissue is described. The use of near infrared (NIR) absorbing nanoshells permits targeted photothermal ablation of tumor tissue via NIR heating of nanoshell-laden tumors using an extracorporeal near infrared source. Human breast carcinoma cells incubated with nanoshells in vitro were found to undergo photothermally induced morbitity upon exposure to NIR light (820 nm, 44 W/cm/sup 2/) as determined using a fluorescent viability stain. Cells without nanoshells displayed no loss in viability after the same periods and conditions of near infrared illumination. Likewise, in vivo studies under MR guidance revealed that exposure to low doses of near infrared light (820 nm, 4 W/cm/sup 2/) in solid tumors treated with metal nanoshells reached average temperatures capable of inducing irreversible tissue damage (/spl Delta/T=37.4/spl plusmn/6.6/spl deg/C) within 4-6 minutes. Controls treated without nanoshells demonstrated significantly less average temperatures upon exposure to near infrared light (/spl Delta/T<10/spl deg/C). These findings demonstrated good correlation with histological findings. Tissues heated above the thermal damage threshold displayed coagulation, cell shrinkage, and loss of nuclear staining-indicators of irreversible thermal damage. Control tissues did not display these indicators and appeared undamaged.

Nanoshells for integrated diagnosis and therapy of cancer

Metal nanoshells are a novel type of composite nanoparticle consisting of a dielectric core covered by a thin metallic shell which is typically gold. Nanoshells possess highly favorable optical and chemical properties for biomedical imaging and therapeutic applications. By varying the relative the dimensions of the core and the shell, the optical resonance of these nanoparticles can be precisely and systematically varied over a broad wavelength region ranging from the near-UV to the mid-infrared. This range includes the near-infrared (NIR) region where tissue transmissivity peaks. In addition, nanoshells offer other advantages over conventional organic dye imaging agents, including improved optical properties and reduced susceptibility to chemical/thermal denaturation. Furthermore, the same conjugation protocols used to bind biomolecules to gold colloid are easily modified for nanoshells. We first review the synthesis of gold nanoshells and illustrate how the core/shell ratio and overall size of a nanoshell influences its scattering and absorption properties. We then describe several examples of nanoshell-based diagnostic and therapeutic approaches including the development of nanoshell bioconjugates for molecular imaging, the use of scattering nanoshells as contrast agents for optical coherence tomography (OCT), and the use of absorbing nanoshells in NIR thermal therapy of tumors.

A rapid, whole blood immunoassay using metal nanoshells

Using metal nanoshells as an immunoassay substrate, we describe an immunoassay capable of detecting blood borne analyte on the order of minutes. Near infrared resonant gold nanoshells were labeled with antibodies specific to rabbit IgG analyte. The antibody-nanoshell conjugates were detectable via near infrared photometry in solution with saline, serum, and whole blood. Addition of analyte induced aggregation of antibody-nanoshell conjugates, causing a decrease in the original nanoshell near infrared resonance. Aggregation proceeded in a concentration dependent fasion in all three mediums (saline, serum, whole blood), permitting quantitative detection of analyte within 10-30 minutes and sensitivities <1 ng/mL.

A rapid, near infrared, whole blood immunoassay using metal nanoshells

The development of a rapid, whole blood immunoassay with the capacity to detect various analytes would greatly benefit point-of-care or public health applications, where there is a strong demand for the rapid, high throughput screening of blood-borne species. Immunoassays, with their high affinity/specificity, show the most promise for implementing such a system. Nevertheless, conventional methods, such as the enzyme linked immunosorbent assays (ELISAs), have failed to develop a robust, rapid, whole blood assay, as they require time-consuming sample purification, incubation, and rinsing steps prior to analysis. We have used a new class of optically-active nanoparticles called metal nanoshells to develop a new rapid, near-infrared (NIR) immunoassay capable of detecting very low concentrations of analytes in whole blood within minutes without any sample preparation.

Photothermal cancer therapy using intravenously injected near-infrared-absorbing nanoparticles

This report focuses on the treatment parameters leading to successful nanoshell-assisted photo-thermal therapy (NAPT). NAPT takes advantage of the strong near infrared (NIR) absorption of gold-silica nanoshells, a new class of nanoparticles with tunable optical absorptivities that are capable of passive extravasation from the abnormal tumor vasculature due to their nanoscale size. Under controlled conditions nanoshells accumulate in tumors with superior efficiency compared to surrounding tissues. For this treatment: (1) tumors were inoculated in immune-competent mice by subcutaneous injection, (2) polyethylene glycol coated nanoshells (≈150 nm diameter) with peak optical absorption in the NIR were intravenously injected and allowed to circulate for 6 - 48 hours, and (3) tumors were then extracorporeally illuminated with a collimated diode laser (808 nm, 2-6 W/cm2, 2-4 min). Nanoshell accumulations were quantitatively assessed in tumors and surrounding tissues using neutron activation analysis for gold. In order to assess temperature elevation, laser therapies were monitored in real-time using a mid-infrared thermal sensor. NAPT resulted in complete tumor regression in >90% of the subjects. This simple, non-invasive procedure shows great promise as a technique for selective photo-thermal tumor treatment.

Nanoshell bioconjugates for integrated imaging and therapy of cancer

Currently, separate diagnostic and therapeutic modalities are required for the diagnosis and treatment of cancer. In many cases, the present standard of care requires invasive surgical procedures and/or other treatments associated with significant side effect profiles, high cost, and poor clinical outcome. A single technology with dual diagnostic/therapeutic capabilities would potentially yield significant savings in the time and cost associated with diagnosing and treating many cancers. In this paper, we discuss gold nanoshell bioconjugates and their role in the development of an integrated cancer imaging and therapy application. Nanoshells are a novel class of nanomaterials that have unique properties including continuous and broad wavelength tunability, far greater scattering and absorption coefficients, increased chemical stability, and improved biocompatibility. Here, we describe the development of an integrated cancer imaging and therapy application using near-infrared (NIR) gold nanoshell bioconjugates.