# Materials Science and Engineering/Cancer Treatment and Materials Science

## Cancer Treatment and Materials Science

### What is Cancer?

Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct growth into adjacent tissue through invasion or by implantation into distant sites by metastasis. Metastasis is defined as the stage in which cancer cells are transported through the bloodstream or lymphatic system. Cancer may affect people at all ages, but risk tends to increase with age, due to the fact that DNA damage becomes more apparent in aging DNA. It is one of the principal causes of death in developed countries.

There are many types of cancer. Severity of symptoms depends on the site and character of the malignancy and whether there is metastasis. A definitive diagnosis usually requires the histologic examination of tissue by a pathologist. This tissue is obtained by biopsy or surgery. Most cancers can be treated and some cured, depending on the specific type, location, and stage. Once diagnosed, cancer is usually treated with a combination of surgery, chemotherapy and radiotherapy. As research develops, treatments are becoming more specific for the type of cancer pathology. Drugs that target specific cancers already exist for several cancers. If untreated, cancers may eventually cause illness and death, though this is not always the case.

The unregulated growth that characterizes cancer is caused by damage to DNA, resulting in mutations to genes that encode for proteins controlling cell division. Many mutation events may be required to transform a normal cell into a malignant cell. These mutations can be caused by chemicals or physical agents called carcinogens, by close exposure to radioactive materials, or by certain viruses that can insert their DNA into the human genome. Mutations occur spontaneously, and may be passed down from one generation to the next as a result of mutations within germ lines. However, some carcinogens also appear to work through non-mutagenic pathways that affect the level of transcription of certain genes without causing genetic mutation.

Many forms of cancer are associated with exposure to environmental factors such as tobacco smoke, radiation, alcohol, and certain viruses. While some of these risk factors can be avoided or reduced, there is no known way to entirely avoid the disease.

From Cancer

### What is Cancer Nanotechnology?

Nanotechnological devices are typically defined as being essentially man-made and in the 1-1000 nm range in at least one dimension.

Below is a list of examples of cancer-related nanotechnologies.

• Liposomes
• Magnetic resonance imaging (MRI) contrast agents
• Nanoparticle-based methods that provide high-specificity detection of DNA and protein

Two main subfields of nanotechnology are nanovectors and patterning of substrates. Devices based on nanotechnology are able to detect many molecular signals and biomarkers in real time. This may yield advances in early detection, diagnostics, prognostics, and selection of therapeutic strategies. Multifunctionality provides ability to specifically deliver therapeutics and imaging agents to cancer sites.

### Nanoparticles

A nanoparticle is a microscopic particle whose size is measured in nanometers (nm). It is defined as a particle with at least one dimension <100nm.

### Properties

Nanoparticles are of great scientific interest as they are effectively a bridge between bulk materials and atomic or molecular structures. A bulk material should have constant physical properties regardless of its size, but at the nano-scale this is often not the case. Size-dependent properties are observed such as quantum confinement in semiconductor particles, surface plasmon resonance in some metal particles and superparamagnetism in magnetic materials.

The properties of materials change as their size approaches the nanoscale and as the percentage of atoms at the surface of a material becomes significant. For bulk materials larger than one micrometre the percentage of atoms at the surface is minuscule relative to the total number of atoms of the material. The interesting and sometimes unexpected properties of nanoparticles are partly due to the aspects of the surface of the material dominating the properties in lieu of the bulk properties.

Nanoparticles exhibit a number of special properties relative to bulk maerial. For example, the bending of bulk copper (wire, ribbon, etc.) occurs with movement of copper atoms/clusters at about the 50 nm scale. Copper nanoparticles smaller than 50 nm are considered super hard materials that do not exhibit the same malleability and ductility as bulk copper. Suspensions of nanoparticles are possible because the interaction of the particle surface with the solvent is strong enough to overcome differences in density, which usually result in a material either sinking or floating in a liquid. Nanoparticles often have unexpected visible properties because they are small enough to scatter visible light rather than absorb it. For example gold nanoparticles appear deep red to black in solution.

### Classification

At the small end of the size range, nanoparticles are often referred to as clusters. Nanospheres, nanorods, and nanocups are just a few of the shapes that have been grown.

Metal, dielectric, and semiconductor nanoparticles have been formed, as well as hybrid structures (e.g., core-shell nanoparticles). Nanoparticles made of semiconducting material may also be labeled quantum dots if they are small enough (typically sub 10nm) that quantization of electronic energy levels occurs. Such nanoscale particles are used in biomedical applications as drug carriers or imaging agents.

Semi-solid and soft nanoparticles have been manufactured. A prototype nanoparticle of semi-solid nature is the liposome. Various types of liposome nanoparticles are currently used clinically as delivery systems for anticancer drugs and vaccines.

### Characterization

Nanoparticle characterization is necessary to establish understanding and control of nanoparticle synthesis and applications. Characterization is done by using a variety of different techniques, mainly drawn from materials science. Common techniques are electron microscopy [TEM,SEM], atomic force microscopy [AFM], dynamic light scattering [DLS], x-ray photoelectron spectroscopy [XPS], powder x-ray diffractometry [XRD], and Fourier transform infrared spectroscopy [FTIR].

### Gold Nanoparticles

#### Introduction

It is possible to create high peak temperatures and microscopic mechanical disruption localized at the cellular level when energy is selectively deposited into particles.

#### Mie Theory

Mie theory, also called Lorenz-Mie theory, is a complete analytical solution of Maxwell's equations for the scattering of electromagnetic radiation by spherical particles (also called Mie scattering). Mie solution is named after its developer German physicist Gustav Mie. However, Danish physicist Ludwig Valentine Lorenz and others independently developed the theory of electromagnetic plane wave scattering by a dielectric sphere.

From Mie Theory

## Light-Absorbing Microparticles and Nanoparticles - 2003

 Selective Cell Targeting with Light-Absorbing Microparticles and Nanoparticles Costas M. Pitsillides, Edwin K. Joe, Xunbin Wei, R. Rox Anderson and Charles P. Lin "We describe a new method for selective cell targeting based on the use of light-absorbing microparticles and nanoparticles that are heated by short laser pulses to create highly localized cell damage. The method is closely related to chromophore-assisted laser inactivation and photodynamic therapy, but is driven solely by light absorption, without the need for photochemical intermediates (particularly singlet oxygen). The mechanism of light-particle interaction was investigated by nanosecond time-resolved microscopy and by thermal modeling. The extent of light-induced damage was investigated by cell lethality, by cell membrane permeability, and by protein inactivation. Strong particle size dependence was found for these interactions. A technique based on light to target endogenous particles is already being exploited to treat pigmented cells in dermatology and ophthalmology. With exogenous particles, phamacokinetics and biodistribution studies are needed before the method can be evaluated against photodynamic therapy for cancer treatment. However, particles are unique, unlike photosensitizers, in that they can remain stable and inert in cells for extended periods. Thus they may be particularly useful for prelabeling cells in engineered tissue before implantation. Subsequent irradiation with laser pulses will allow control of the implanted cells (inactivation or modulation) in a noninvasive manner."

## The Use of Gold Nanoparticles to Enhance Radiotherapy in Mice - June 2004

 The use of gold nanoparticles to enhance radiotherapy in mice James F Hainfeld, Daniel N Slatkin and Henry M Smilowitz "Mice bearing subcutaneous EMT-6 mammary carcinomas received a single intravenous injection of 1.9 nm diameter gold particles (up to 2.7 g Au/kg body weight), which elevated concentrations of gold to 7 mg Au/g in tumours. Tumour-to-normal-tissue gold concentration ratios remained ∼8:1 during several minutes of 250 kVp x-ray therapy. One-year survival was 86% versus 20% with x-rays alone and 0% with gold alone. The increase in tumours safely ablated was dependent on the amount of gold injected. The gold nanoparticles were apparently non-toxic to mice and were largely cleared from the body through the kidneys. This novel use of small gold nanoparticles permitted achievement of the high metal content in tumours necessary for significant high-Z radioenhancement."

### Nanocages

Nanocages are hollow porous gold nanoparticles ranging in size from 10 to over 150 nm. They are created by reacting silver nanoparticles with chloroauric acid (HAuCl4) in boiling water. While gold nanoparticles absorb light in the visible spectrum of light (at about 550 nm), gold nanocages absorb light in the near-infrared, where biological tissues absorb the least light. Because they are also biocompatable, gold nanocages are promising as a contrast agent for optical coherence tomography, which uses light scattering in a way analogous to ultrasound to produce in-vivo images of tissue with resolution approaching a few micrometres. A contrast agent is required if this technique will be able to image cancers at an early, more treatable stage. Gold nanocages also absorb light and heat up, killing surrounding cancer cells. The Xia group at the University of Washington, the original inventors of the nanocages, has functionalized nanocages with cancer-specific antibodies so they specifically attach to cancer cells.

From Nanocages

Nanoscale cages consisting of gold can be engineered to interact with light. They can be used to image molecular events in live cells and tissues using optical coherence tomography (OCT). The optical properties of nanocages are due to plasmons. When light strikes a plasmon oscillating at a compatible frequency, energy from light is harvested by the plasmon. It is scattered and converted to photons or absorbed and converted to phonons.

## Replacement Reaction between Silver Nanostructures and Chloroauric Acid - March 2004

 Mechanistic study on the replacement reaction between silver nanostructures and chloroauric acid in aqueous medium. Sun Y, Xia Y. "The replacement reaction between silver nanostructures and an aqueous HAuCl(4) solution has recently been demonstrated as a versatile method for generating metal nanostructures with hollow interiors. Here we describe the results of a systematic study detailing the morphological, structural, compositional, and spectral changes involved in such a heterogeneous reaction on the nanoscale. Two distinctive steps have been resolved through a combination of microscopic and spectroscopic methods. In the first step, silver nanostructure (i.e., the template) is dissolved to generate gold atoms that are deposited epitaxially on the surface of each template. Silver atoms also diffuse into the gold shell (or sheath) to form a seamless, hollow nanostructure with its wall made of Au-Ag alloys. The second step involves dealloying, a process that selectively removes silver atoms from the alloyed wall, induces morphological reconstruction, and finally leads to the formation of pinholes in the walls. Reaction temperature was found to play an important role in the replacement reaction because the solubility constant of AgCl and the diffusion coefficients of Ag and Au atoms were both strongly dependent on this parameter. This work has enabled us to prepare metal nanostructures with controllable geometric shapes and structures, and thus optical properties (for example, the surface plasmon resonance peaks could be readily shifted from 500 to 1200 nm by controlling the ratio between Ag and HAuCl(4))."

## Gold Nanocages: Bioconjugation and Their Potential Use as Optical Imaging Contrast Agents - January 2005

 Gold Nanocages: Bioconjugation and Their Potential Use as Optical Imaging Contrast Agents Jingyi Chen, Fusayo Saeki, Benjamin J. Wiley, Hu Cang, Michael J. Cobb, Zhi-Yuan Li, Leslie Au, Hui Zhang, Michael B. Kimmey, Xingde Li, and Younan Xia "Gold nanocages of ${\displaystyle <40nm}$ in dimension have been synthesized using the galvanic replacement reaction between Ag nanocubes and HAuCl4 in an aqueous solution. By controlling the molar ratio between Ag and HAuCl4, the gold nanocages could be tuned to display surface plasmon resonance peaks around ${\displaystyle 800nm}$, a wavelength commonly used in optical coherence tomography (OCT) imaging. OCT measurements on phantom samples indicate that these gold nanocages have a moderate scattering cross-section of ~${\displaystyle 8.10\cdot 10^{-16}m^{2}}$ but a very large absorption cross-section of ~${\displaystyle 7.26\cdot 10^{-15}m^{2}}$, suggesting their potential use as a new class of contrast agents for optical imaging. When bioconjugated with antibodies, the gold nanocages have also been demonstrated for specific targeting of breast cancer cells."

## Shape-Controlled Synthesis of Silver and Gold Nanostructures - May 2005

 Shape-Controlled Synthesis of Silver and Gold Nanostructures Benjamin Wiley, Yugang Sun, Jingyi Chen, Hu Cang, Zhi-Yuan Li, Xingde Li, and Younan Xia "This article provides a brief account of solution-phase methods that generate silver and gold nanostructures with well-controlled shapes. It is organized into five sections: The first section discusses the nucleation and formation of seeds from which nanostructures grow. The next two sections explain how seeds with fairly isotropic shapes can grow anisotropically into distinct morphologies. Polyol synthesis is selected as an example to illustrate this concept. Specifically, we discuss the growth of silver nanocubes (with and without truncated corners), nanowires, and triangular nanoplates. In the fourth section, we show that silver nanostructures can be transformed into hollow gold nanostructures through a galvanic replacement reaction. Examples include nanoboxes, nanocages, nanotubes (both single- and multi-walled), and nanorattles. The fifth section briefly outlines a potential medical application for gold nanocages. We conclude with some perspectives on areas for future work."

## Gold Nanocages: Engineering Their Structure for Biomedical Applications - July 2005

 Gold Nanocages: Engineering Their Structure for Biomedical Applications J. Chen, B. Wiley, Z.-Y. Li, D. Campbell, F. Saeki, H. Cang, L. Au, J. Lee, X. Li, Y. Xia "The galvanic replacement reaction between a Ag template and HAuCl4 in an aqueous solution transforms 30-200 nm Ag nanocubes into Au nanoboxes and nanocages (nanoboxes with porous walls). By controlling the molar ratio of Ag to HAuCl4, the extinction peak of resultant structures can be continuously tuned from the blue (400 nm) to the near-infrared (1200 nm) region of the electromagnetic spectrum. These hollow Au nanostructures are characterized by extraordinarily large cross-sections for both absorption and scattering. Optical coherence tomography measurements indicate that the 36 nm nanocage has a scattering cross-section of ${\displaystyle 0.8\cdot 10^{-15}m^{2}}$ and an absorption cross-section of ${\displaystyle 7.3\cdot 10^{-15}m^{2}}$. The absorption cross-section is more than five orders of magnitude larger than those of conventional organic dyes. Exposure of Au nanocages to a camera flash resulted in the melting and conversion of Au nanocages into spherical particles due to photothermal heating. Discrete-dipole-approximation calculations suggest that the magnitudes of both scattering and absorption cross-sections of Au nanocages can be tailored by controlling their dimensions, as well as the thickness and porosity of their walls. This novel class of hollow nanostructures is expected to find use as both a contrast agent for optical imaging in early stage tumor detection and as a therapeutic agent for photothermal cancer treatment."

## Gold Nanostructures: Engineering Their Plasmonic Properties for Biomedical Applications - September 2006

 Gold nanostructures: engineering their plasmonic properties for biomedical applications Min Hu, Jingyi Chen, Zhi-Yuan Li, Leslie Au, Gregory V. Hartland, Xingde Li, Manuel Marquez and Younan Xia "The surface plasmon resonance peaks of gold nanostructures can be tuned from the visible to the near infrared region by controlling the shape and structure (solid vs. hollow). In this tutorial review we highlight this concept by comparing four typical examples: nanospheres, nanorods, nanoshells, and nanocages. A combination of this optical tunability with the inertness of gold makes gold nanostructures well suited for various biomedical applications."

### Nanoshells

#### Introduction

A gold layer covered with silica is a metal-based nanovector that is an example of a nanoshell. Thickness of a gold layer is adjusted such that the nanoshell can be selectively activated through tissue irradiation with near-IR light. Localized therapeutic thermal ablation can be performed. This is an example of a nanovector that is highly selective and externally activated.

#### Optical properties

Development of chemical synthesis, planar nanostructure fabrication, and accurate numberical methods have provided building blocks for guiding, controlling, and manipulating light at the nanometer scale. Optical properties are controlled by plasmon resonance of the metallic nanosctructures. Resonance of a nanoshell is very sensitive to inner and outer dimensions of the metallic shell layer. Plasmon-resonant particles follow an analogue of molecular orbital theory. There is hybridization in the same manner as individual wave functions of simple molecules. There is a "design rule" of metallic nanostructures that allows prediction of optical resonant properties. The infrared spectrum is associated with light with frequency between ${\displaystyle 4000}$ and ${\displaystyle 400cm^{-1}}$ (${\displaystyle 2500-25000nm}$). The plasmon resonance of nanoshells in the the near-infrared region of the spectrum has enabled various biomedical applications. The internal geometry of a dielectric core-metal shell nanoparticle controls the far-field electromagnetic response. The local electromagnetic field at the nanoshell surface is controlled by its geometry.

#### Size and Shape

By precisely controlling dimensions of metallic nanostructures of certain shapes, the wavelengths at which they absorb or scatter light can be controlled. Plasmon resonance frequency in metals is a function of the type and shape of metal. The optical resonance of solid metallic nanospheres is a fixed frequency resonance. The plasmon resonance of solid metallic nanoparticles varies only weakly with particle size; longer wavelengths are absorbed as particle size is increased. The aspect ratio of a metallic nanorod defines distinct plasmon resonance frequencies associated with longitudinal and transverse dimensions of the nanostructure. Spectrally distinct multiple resonance appear in the nanoshell spectrum by keeping the core-shell ratio constant by increasing the total nanoparticle size. There is a unique light-scattering signature associated with each resonance and can be easily measured. Particles become better scatterers than absorbers of light with increasing particle size. An overall redshift in hybridized plasmon modes can be seen with increasing nanoparticle size.

The longitudinal plasmon is shifted to longer wavelengths as length is increased. The dielectric environment is also important.

Comparing single nanoshells to single quantum dots, the absorption of nanoshells is typically ${\displaystyle 10^{6}}$ larger absorption cross section, which is nominally five time the physical cross section of the nanoparticle.

 Inner core Outer shell Peak absorption Source ${\displaystyle 120nm}$ ${\displaystyle 10nm}$ ${\displaystyle 800nm}$ Immunotargeted Nanoshells for Integrated Cancer Imaging and Therapy ${\displaystyle 60nm}$ ${\displaystyle 20nm}$ ${\displaystyle 750nm}$ Nanoshell-Enabled Photonics-Based Imaging and Therapy of Cancer ${\displaystyle 60nm}$ ${\displaystyle 10nm}$ ${\displaystyle 850nm}$ Nanoshell-Enabled Photonics-Based Imaging and Therapy of Cancer ${\displaystyle 60nm}$ ${\displaystyle 7nm}$ ${\displaystyle 920nm}$ Nanoshell-Enabled Photonics-Based Imaging and Therapy of Cancer ${\displaystyle 60nm}$ ${\displaystyle 5nm}$ ${\displaystyle 1020nm}$ Nanoshell-Enabled Photonics-Based Imaging and Therapy of Cancer

#### Plasmon hybridization

Plasmon response of metal-based nanostructures is understood as the interaction of "hybridization" of plasmons supported by metallic nanostructures. This picture can be used to describe the structural tunability of nanoshells; there is an interactino between two fixed-frequency plasmons supported by a nanoscale sphere and nanoscale cavity. Nanoshell plasmons correspond to a "bonding" plasmon and a higher-energy "anti-bonding" plasmon. Only the lower energy plasmon interacts strongly with an incident optical field.

The nanoshell plasmon shifts to lower energies as shell thickness is decreased. This is due to an increased interaction between the sphere and cavity plasmons, resulting in an increased splitting between two hybrid plasmons of the nanoshell. Plasmon hybridization provides a simple, powerful and general principle used to guide the design of metallic nanostructures and predict plasmon response qualitatively and quantitatively.

The variation of the core diameter and shell layer thickness of a nanoshell can be used to "tune" the local electromagnetic field at the nanoparticle surface in a manner that directly controls the SERS response of molecules absorbed on the surface.

#### Characterization

Raman spectroscopy at near infrared wavelengths is highly desirable in probing chemically complex environments because unwanted background fluorescence from molecules is drastically reduced. Raman scattering is a much weaker effect at infrared wavelengths than when pumped with visible light.

The size of the core and the shell of a nanoshell can be varied independently. Plot the nanoshell Raman response in "core-shell" space to determine the optimum dimensions of a nanoshell with maximum SERS enhancement.

Nanoshells can be dispersed and bound to a glass substrate, which facilitates exposure to multiple solvents and rinsing procedures.

#### Surrounding Medium

Two effects are associated with an increase of the index of refraction in a surrounding medium.

• Shifting of nanoshell dipolar plasmon to longer wavelengths
• Increase in the quadraupole plasmon resonance relative to dipole plasmon resonance in the nanoshell spectrum

Strengthening of the quadrupole plasmon resonance is due to phase retardation effects. Nanoparticle appears larger relative to reduced spatial wavelength of incident light when the dielectric constant of the embedding medium is increased.

The magnitude of the SPR shift upon increase in the refractive index of the embedding medium increases with the overall size of the nanoparticle. The shift is also dependent upon the core-shell ratio, and is most sensitive in the thin-shell limit of the nanostructure's internal geometry.

#### Biomedical Applications of Nanoshells

There are high biocompatibility characteristics of gold, and the near-infrared region of the spectrum is the region of highest physiological transmissivity. Blood and tissue are most transparent, and light can penetrate tissue at a distance of 10 cm or more. A photothermal response can be exploited as a potential strategy for cancer therapy.

Localized, irreversible photothermal ablation of tumor tissue was successfully achieved both in vitro and in vivo. Combining nanoshells with infrared light exposure results in localized cell death in the region of laser irradiation. An experiment can be monitored with MRI-based temperature mapping technique. Infrared laser fluences that would normally induce temperature increases of less than ${\displaystyle 10^{\circ }}$ without nano-shells present produced temperature increases of more than ${\displaystyle 37^{\circ }}$ with the same exposure time. Tumor pathology suggests that irreversible tissue damage coincides with measurable photothermal temperature increase. There is significant promise of a simple, noninvasive treatment as a technique of selective photothermal tumor ablation.

## Nanoshell-mediated near-infrared thermal therapy of tumors - November 2003

 Nanoshell-mediated near-infrared thermal therapy of tumors under magnetic resonance guidance L. R. Hirsch, R. J. Stafford, J. A. Bankson, S. R. Sershen, B. Rivera, R. E. Price, J. D. Hazle, N. J. Halas, J. L. West Human breast carcinoma cells incubated with nanoshells in vitro were found to have undergone photothermally induced morbidity on exposure to NIR light (820 nm, 35W�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 created with metal nanoshells reached average maximum temperatures capable of inducing irreversible tissue damage (Delta T = 37.4 +/- 6.6°C) within 4–6 min. Controls treated without nanoshells demonstrated significantly lower average temperatures on exposure to NIR light (Delta T < 10°C). These findings demonstrated good correlation with histological findings.

## Photo-thermal tumor ablation mice using near infrared-absorbing nanoparticles - February 2004

 Photo-thermal tumor ablation in mice using near infrared-absorbing nanoparticles [9] D. Patrick O'Neala, Leon R. Hirschb, Naomi J. Halasc, J. Donald Paynea and Jennifer L. West "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 (≈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."

## Nanoshell-Enabled Photonics-Based Imaging and Therapy of Cancer - February 2004

 Nanoshell-Enabled Photonics-Based Imaging and Therapy of Cancer Christopher Loo, Alex Lin, Leon Hirsch, Min-Ho Lee, Jennifer Barton, Naomi Halas, Jennifer West, Rebekah Drezek "In this article, we first review the synthesis of gold nanoshells and illustrate how the core/shell ratio and overall size of a nanoshell influence its scattering and absorption properties. We then describe several examples of nano-shell 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."

## Immunotargeted Nanoshells for Integrated Cancer Imaging and Therapy - March 2005

 Immunotargeted Nanoshells for Integrated Cancer Imaging and Therapy [11] Christopher Loo, Amanda Lowery, Naomi Halas, Jennifer West, Rebekah Drezek "First demonstration of coupling a bioimaging application to a cancer therapy application using nanoshells targeted against a clinically relevant biomarker"

## Tuning the Optical Resonant Properties of Metallic Nanoshells - May 2005

 Superparamagnetic iron oxide contrast agents: physiochemical characteristics and applications in MR imaging [12] Yi-Xiang J. Wang, Shahid M. Hussain, Gabriel P. Krestin Titles of sections are below Introduction Tunable Plasmons with Nanoshell Geometry Surface Enhanced Raman Scattering Optimized on Nanoshell Substrates Nanoshell Surface Plasmon Resonance (SPR) Sensors

## Plasmonic photothermal therapy (PPTT) using gold nanoparticles

Photothermal therapy: light absorbing dyes to damage tumors photothermally

Photodynamic therapy: chemical photosensitizers generate oxygen that can destroy tumors

### Iron Oxide

Iron oxide may be used as a tool in thermal therapy of tumors. A first paper was published in 1957 regarding the use of iron oxide particles and heating in medical applications.

## Selective Inductive Heating of Lymph Nodes - October 1957

 Selective Inductive Heating of Lymph Nodes [13] J. van der Zee

## A Mathematical Model of High Frequency Heating - February 2001

 Problems in the Local Hyperthermia of Inductively Heated Embolized Tissues [14] J. van der Zee

## Intracellular and Extracellular Hyperthermia - May 2002

 Is intracellular hyperthermia superior to extracellular hyperthermia in the thermal sense? [15] Y. Rabin

## Heating the patient: a promising approach? - May 2002

 Heating the patient: a promising approach? [16] J. van der Zee

## Heating potential of iron oxides - February 2002

 Heating potential of iron oxides for therapeutic purposes in interventional radiology [17] Hilger I, Fruhauf K, Andra W, Hiergeist R, Hergt R, Kaiser WA

## Hyperthermia in combined treatment of cancer - July 2002

 Hyperthermia in combined treatment of cancer [18] ProfessorP Wusta, B Hildebrandtb, G Sreenivasaa, B Rauc, J Gellermanna, H Riessb, R Felixa and PM Schlagc

## Applications of Magnetic Nanoparticles in Biomedicine - June 2003

 Applications of magnetic nanoparticles in biomedicine [19] Q A Pankhurst, J Connolly, S K Jones and J Dobson

## Magnetic Nanoparticle Heating - February 2005

 Use of magnetic nanoparticle heating in the treatment of breast cancer [20] Hilger, I. Hergt, R. Kaiser, W.A. Related article from National Cancer Institute: Magnetic Nanoparticle Heaters Kill Breast Cancer Cells, April 25, 2005

## Folate-Conjugated Iron Oxide Nanoparticles - July 2005

 Folate-Conjugated Iron Oxide Nanoparticles for Solid Tumor Targeting as Potential Specific Magnetic Hyperthermia Mediators: Synthesis, Physicochemical Characterization, and in Vitro Experiments [21] Sonvico F, Mornet S, Vasseur S, Dubernet C, Jaillard D, Degrouard J, Hoebeke J, Duguet E, Colombo P, Couvreur P New folate-conjugated superparamagnetic maghemite nanoparticles have been synthesized for the intracellular hyperthermia treatment of solid tumors. These ultradispersed nanosystems have been characterized for their physicochemical properties and tumor cell targeting ability, facilitated by surface modification with folic acid. Preliminary experiments of nanoparticles heating under the influence of an alternating magnetic field at 108 kHz have been also performed. The nanoparticle size, surface charge, and colloidal stability have been assessed in various conditions of ionic strength and pH. The ability of these folate “decorated” maghemite nanoparticles to recognize the folate receptor has been investigated both by surface plasmon resonance and in folate receptor expressing cell lines, using radiolabeled folic acid in competitive binding experiments. The specificity of nanoparticle cellular uptake has been further investigated by transmission electron microscopy after incubation of these nanoparticles in the presence of three cell lines with differing folate receptor expression levels. Qualitative and quantitative determinations of both folate nanoparticles and nontargeted control nanoparticles demonstrated a specific cell internalization of the folate superparamagnetic nanoparticles. Related article from National Cancer Institute: Targeted Magnetic Nanoparticles Heat Tumors to Death, October 10, 2005 Reporting its work in the journal Bioconjugate Chemistry, a research team headed by Patrick Couvreur, Ph.D., describes its studies in which the investigators use folic acid to target magnetic nanoparticles to tumor cells. Once the tumor cells engulfed the nanoparticles, the researchers then heated the nanoparticles with a rapidly oscillating magnetic field. Preliminary data from these experiments suggest that the nanoparticles should be able to heat up cells beyond 43 °C – a known lethal temperature – after being in the oscillating magnetic field for 20 minutes.

Iron oxide is also used as a contrast agent.

## Superparamagnetic iron oxide contrast agents - November 2001

 Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging Yi-Xiang J. Wang, Shahid M. Hussain, Gabriel P. Krestin Superparamagnetic iron oxide MR imaging contrast agents have been the subjects of extensive research over the past decade. The iron oxide particle size of these contrast agents varies widely, and influences their physicochemical and pharmacokinetic properties, and thus clinical application. Superparamagnetic agents enhance both T1 and T2/T2* relaxation. In most situations it is their significant capacity to reduce the T2/T2* relaxation time to be utilized. The T1 relaxivity can be improved (and the T2/T2* effect can be reduced) using small particles and T1-weighted imaging sequences. Sections: Introduction Physicochemical characteristics of superparamagnetic iron oxide agents Classification of superparamagnetic iron oxide agents Application of superparamagnetic iron oxide agents in reticuloendothelial system imaging Application of superparamagnetic iron oxide agents for bowel contrast Application of superparamagnetic iron oxide agents for MR angiography Application of superparamagnetic iron oxide agents for tissue perfusion imaging Superparamagnetic iron oxide agents for receptor-directed MR imaging and magnetically labeled cell probe MR imaging Conclusion