Nanotechnology in Medicine
Applications of nanotechnology to medicine are among the first being delivered to the market.
The National Institute of Health (NIH) has defined a roadmap for developing the field of nanomedicine.
The NIH initiative for nanomedicine involves the creation of instruments and materials for the purpose of intervening at the molecular scale to diagnose, cure, and prevent diseases.
Just as nanomaterials can perform mechanical and electrical functions, they can also be used to improve human life with medicine.
Among the most researched concepts in nanomedicine are diagnostics, enhanced medical imaging, gene therapy, and efficient drug delivery.
Diagnosing diseases
Quantum dots
In simple terms a quantum dot is a small semiconductor crystal, with size usually ranging from 2 – 10 nm.
Due to its atomic composition and size, quantum dots exhibit unique and useful properties.
One attribute that has made them the focus of interest in the medical community is their luminescent property.
In short, these quantum dots efficiently emit a range of radiation, infrared to ultraviolet, with extreme precision.
For more detailed information, see page 2 of the NanOU Educational page.
A Revolution in Detection
Currently organic fluorophores are key to the primary methods used in cancer and tumour detection.
The current methods used which allow the dyes to seek out cancerous growth rely on bonding specialized antibodies or biomolecules to them which search for, and attach to, the target tissue, cell or tumour.
After the target has been located these traditional dyes are stimulated by a somewhat specific range of wavelengths which excite them to fluoresce after which the area in question can be scanned.
Some of the primary shortcomings of the traditional dyes are their high sensitivity to biological environments and a likelihood that they will undergo a photooxidation process which permanently destroys their functionally, called photobleaching.
Overcoming Old Problems
Quantum dots have already in part addressed many of the shortcomings of traditional dyes.
Due to the development of quantum dot coatings aimed to avoid the leaching of toxic components into the subject’s system, they have become not only safe to use, but also substantially more stable than the traditional dyes.
Additionally, quantum dots have a much higher efficiency than traditional dyes: the ratio of radiation applied to the quantum dots vs. radiation emitted from them is much better, allowing brighter, clearer imaging.
Benefits and Potential of quantum dots
Due to the precise manufacturing techniques currently available there is a very high degree of control over the
wavelength of the radiation emitted by the quantum dots.
It is this property which could allow for multiple quantum dot
“tags”, (alternate colors) to be used simultaneously to target several different areas of interest.
Another benefit of quantum dots is the precise size control which provides the ability to adjust size to allow necessary locator antibodies, or cancer fighting drugs, which could be released to destroy the tumour when it is has been located.
This increased sensitivity and brighter output could also allow for the location of very early stage tumours, which is vital in stopping the spread and development of the disease.
Many current treatments in use remain primarily effective only during the early stages of cancerous growth and not with developed cancers.
More information on the quantum dots in drug delivery and cancer treatment is given below.
Coating and quantum dot composition are both intense areas of focus for current research.
The most common coatings are polymer based layers applied during synthesis of the seimconducting crystals.
As more diverse coatings are explored, the potential for attaching cancer fighting drugs, and locators, via molecular bonding are rapidly increasing.
Also, although CdSe is the most common composition of crystal currently used, research emphasis is being placed on other molecules to probe the most cost effective, realistically available material which could be mass produced while still yielding the desired properties.
In addition to their use for cancer detection and treatment quantum dots offer the potential to study cellular processes with accuracy and depth not yet available using current observation methods.
By changing the targeting device on the quantum dot any cell or molecule could potentially be located and studied, and with the long life of quantum dots they could provide immense insight into many currently undescribed biological processes.
Medical imaging enhancement
Several different imaging techniques are employed in healthcare today.
Among the most used methods are X-rays, magnetic resonance imaging (MRI), computed tomography (CT), and single-photon emission computed tomography (SPECT).
By combining these systems with special nanoparticles, doctors are able to obtain more detailed, clearer images of reality that will provide critical information for a correct diagnosis.
Consider small developing tumor in the brain.
With a traditional MRI, the tumor may not be distinguishable from the surrounding brain tissue.
One of the problems with dealing with the central nervous system (CNS) is the blood brain barrier (BBB) and the small 25 nm passageways through the brain.
Nanoparticles attracted to tumor specific antigens can easily penetrate the BBB and congregate at the tumor site.
When obtaining the MRI images, then, the nanoparticles provide more feedback, detailing the outline of the tumor.
MRI Operation: an overview
In magnetic resonance imaging, external magnetic field sources placed around the body are used to manipulate the magnetic moment of hydrogen protons in the body.
When one of these external fields is turned off, the hydrogen protons resonate (i.e. the magnetic moment spins) back to its equilibrium position.
As each proton resonates, radio frequency (RF) signals are emitted.
Different tissues are different shades as a result of the varying lengths of resonation and the attenuation of the emitted RF signals. &nbps;
The RF signals are detected by receivers which transform the RF signals into voltage data. &nbpsp;
Hydrogen is used to image body tissue because the majority of tissue is composed of water.
About 63% of the body is hydrogen, which is more than twice as much as the next most abundant element, oxygen.
The hydrogen proton possesses a discrete spin as described quantum mechanics.
The spin of a proton results in a magnetism or, more specifically, a magnetic moment, which is aligned along the axis of rotation.
It is the movement of the magnetic moment which the MRI machine detects.
To understand MRIs, it is important to define a reference
frame.
The +Z-axis lies along the axis of the individuals body, extending from the feet through the head in the center of the MRI machine.
The XY plane, being perpendicular to the Z direction, describes the position within a particular slice across the subject being imaged.
The first step in the imaging process is to apply the primary magnetic field.
The primary magnetic field, commonly known as
B0, is applied along the +Z-axis.
B
0 is a strong, uniform field which is typically on the order of 1.5 Tesla.
This strong field has the effect of polarizing all hydrogen protons along either the +Z-axis or the -Z-axis.
The substantial net magnetization, though, lies along the +Z-axis due to the direction of the primary field.
The next step in the imaging process is to apply an RF magnetic field which is transverse or perpendicular to the B
0 along the Z-axis.
Usually, this field is applied along the x-direction and is called B
1.
The B
1 field is crutial because it induces the movement of the proton's magnetic moment.
If the B
1 field along the x-direction is applied for a specific amount of time, the magnetic moments will be aligned along the y-axis (due to the right-hand rule).
The RF pulse which moves the spin of the protons into the XY plane is known as the π/2 pulse or RF excitation (the term π/2 is used because it is the radian equivalent of a 90° rotation from the Z-axis to the XY plane).
As both B
0 and
1 are applied, the magnetic moment now spins in the XY plane perpendicular to Z-axis.
It turns out that the moment spins at a frequency proportional to the strength of the magnetic field (ω = γB, where ω is known as the Larmor frequency and γ is the gyrometric ration of the proton).
The Larmor frequency is very important.
As the X and Y component of the magnetic moment change, a time-varying RF magnetic field is emitted into detection coils of the MRI machine.
The RF signals passing through the coil induces a voltage in the coils.
The frequency of the induced voltages, then, must also be the Larmor frequency.
Therefore, the RF excitation is crutial because it induces the movement of the magnetic moment, allowing the protons to remotely produce a voltage which can then be analyzed.
It is the voltage induced by the motion of the magnetic moment which allows the MRI image to be produced.
After the π/2 pulse has been removed, the magnetic moment begins to move back to its original state of lower energy.
Since the B
0 field is always on, the moments will eventually be aligned along the Z-axis once again.
In returning to their original state, the magnetic moments follow a path of
precession or rotation around the Z-axis.
The movement of the moments is governed by an equation known as the
Bloch equation.
The solution to the Bloch equation details how the magnetic moment decays with respect to the x, y, and z axes.
The rate of this decay and detection of the induced magnetic field during procession is the basis of MRI image production.
Time constants, T1 and T2, affect how quickly the magnetic moments will decay along the Z-axis or in the XY plane, respectively.
The hydrogen protons in different tissues possess various decay constants (T1 and T2).
Larger values of T1 and T2 lengthen the time of decay as the magnetic momemnts precess about the Z-axis, but smaller values shorten the decay time.
If T1 is
larger than T2, the moment's X-axis and Y-axis components will decay faster than the Z-axis component, so the moment will reach the Z-axis before the Z-component of the moment has reached its steady-state value.
If T2 is
larger than T1, the magnetic moment's Z-axis component will decay faster then the X and Y components.
Consider a coil placed around the x-axis.
As the x component of the magnetic moment decays over time (by constant T2) during the proton's precession around the z-axis, the induced
voltage also decays over time.
As different tissues exhibit different time constants, the induced voltage signal will decay at different rates.
Based on how much voltage signal remains after a certain time has passed, an image pixel will be darker or lighter.
For example, if a tissue has a small T2, the voltage signal may very well decay completely at the time the data is taken.
Since there is a negligible voltage, the image will appear dark.
On the other hand, if the voltage is not negligible (due to a larger T2) at the time the voltage data is retrieved, then the image will have a lighter shade.
MRI enhancement with nanotechnology
Where does nanotechnology fit into the big picture of magnetic resonance imaging?
Research has shown that certain nanoparticles can improve the contrast in MRI images.
More detail present in enhanced images will allow doctors to make a more precise, accurate diagnosis of a patient's condition.
One of the most widely researched variety of nanoparticles has been the superparamagnetic iron oxide (SPIO) nanoparticle.
Superparamagnetism is a phenonemon which causes the magnetic field of the nanoparticles to fluctuate randomly below the Curie temperature (if the fields of the particles start to fluctuate above the this temperature, the particles are paramagnetic).
By themselves, the SPIO nanoparticles are magnetic, but in the presence of sufficient amounts of thermal energy (i.e. room temperature) the nanoparticles' magnetic fields start fluctuating.
Therefore, a solution of SPIO nanoparticles as a whole would have negligible net magnetic field.
However, when an external magnetic field is applied, the nanoparticles can overcome the randomization effect and align to the magnetic field direction just as hydrogen protons do.
Herein lies the benefit of the SPIO particles.
Because they are intrinsically magnetic, they respond to the external magnetic field more quickly than the hydrogen protons.
In other words, the nanoparticles exhibit a smaller T2 relaxation constant.
Comparing the response of an SPIO nanoparticle to that of the hydrogen proton, the X and Y components of the SPIO particle will reach equilibrium faster than the proton.
The corresponding induced
voltages in the detection coils reflect the attenuation of the magnetic moments.
At the point of data acquisition, then, the voltage due to the nanoparticles' emitted RF signals is completely attenuated.
However, the normal contrast present from the hydrogen protons is not lost.
Wherever SPIO particles are located, the resulting MRI image will appear dark.
The other advantage of SPIO nanoparticles is their size and ability to target important organs and locations of cancer.
SPIO nanoparticles can be covered with various molecules which naturally bind to receptors found in cancerous tumors.
MRI technicians will typcially take a pre-contrast image to compare with a post-contrast image.
After taking the pre-contrast image, the patient is given a dose of the functionalized SPIO nanoparticles.
Time is given for the nanoparticles to accumulate in and around the targeted site.
The post-contrast image is then taken and compared to the pre-contrast image, and any differences are flagged appropriately.
With the SPIO nanoparticles, tumors can be imaged much sooner to prevent further metastasis and damage.
SPIO nanoparticles can also be used evaluate the effectiveness of drug delivery.
Common drug delivery systems, such as dendrimers and liposomes, can be combined with SPIO nanoparticles for the purpose of tracking a drug.
MRI images taken after the drug has been administered will show the drug's position in the body with respect to the targeted location.
The images will reveal if the drug has been properly released at the correct location.
Consider this
example which shows the lack of accuracy in drug delivery to a lymph node.
Precision pinpointing and efficient elimination
Conventional drug delivery techniques involve liposomes, polymer micelles, and dendrimers.
Each of these methods have been improved through decreasing the size of the drug carrier to the nanoscale.
Liposomes
As the name suggests, a liposome is a body (soma) with a cavity created by a fat (lipid) membrane.
In many cases, the cavity contains the drug molecules dissolved in an acqueous solution.
The drug is delivered when the lipsomes's lipid membrane fuses with a cell membrane.
The liposome can also be delivered to specific pH regions for more specific action.
The pH of the solution inside the liposome can be made different than the pH surrounding the liposome.
The surrounding solution neutralizes the pH inside the liposome, allowing the drug to diffuse from the liposome to the immediate environment.
Polymer micelles
A micelle is an aggregation of molecules, typically in an aqueous solution, to form a sphere of molecule.
Molecules that make up micelles have a polar head and a non-polar tail and are typically long
chains of hydrocarbons with a polar substituent at one end.
When a molecule with these properties is placed in an aqueous solution, the polar end is attracted to the polar water molecules, while the non-polar end is repelled by the polar water molecules.
The result is that the non-polar tails clump together, forming a sphere-like micelle with the polar end as the surface of the
sphere.
This isolates the hydrophobic end from the surrounding solution and allows the drug to be imbedded in the core of the micelle for delivery.
Dendrimers
Dendrimer comes from a greek word meaning "tree."
The dendrimer is a larger molecule with symmetrical branches.
A dendrimer possesses some excellent properties for drug delivery.
The outer edges of the dendrimer allow the properties of the dendrimer to copy its surrounding environment.
For example, the inner core of the dendrimer may contain a hydrophobic drug, but if the surface of the dendrimer is hydrophilic, it will still dissolve in an aqueous solution.
The dendrimer's size and weight can be tailored for the desired application, and it is also capable of carry larger amounts of drug than most other drug delivery methods.
Though conventional drug delivery methods have proved to be useful, research with newer nanomaterials shows promising results.
Quantum Dots
Quantum dots are semiconducting nanocrystals, which range in size from 2 nm to 10 nm.
They can be used for both diagnosis and drug delivery, especially for
cancer treatments.
By coating the quantum dot with a protective layer that is laced with a cancer-fighting drug, bio-compatibility molecules, and antibodies that stick only to a specific type of cancer, the QD is made ready for injection.
The QD enters the bloodstream and attaches itself to a cancer cell using the antibodies.
The cancer cell takes in the QD, and the location is radiated with infrared light.
This causes the QD to emit photons, allowing the site of the tumor to be located, and release the anti-cancer drug directly into the cancer cell.