Materials Science and Engineering/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].

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

Literature
Light-Absorbing Microparticles and Nanoparticles - 2003

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

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.

From Gold Nanocages as Optical Imaging Contrast Agents

Replacement Reaction between Silver Nanostructures and Chloroauric Acid - March 2004

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

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

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

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

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 $$4000$$ and $$400 cm^{-1}$$ ($$2500 - 25000 nm$$). 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 $$10^6$$ larger absorption cross section, which is nominally five time the physical cross section of the nanoparticle.

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 $$10^{\circ}$$ without nano-shells present produced temperature increases of more than $$37^{\circ}$$ 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

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

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

Immunotargeted Nanoshells for Integrated Cancer Imaging and Therapy - March 2005

Tuning the Optical Resonant Properties of Metallic Nanoshells - May 2005

Plasmonic photothermal therapy (PPTT) using gold nanoparticles

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

A Mathematical Model of High Frequency Heating - February 2001

Intracellular and Extracellular Hyperthermia - May 2002

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Iron oxide is also used as a contrast agent.

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