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Nanomedicines

Nanomedicine is the medical application of nanotechnology. The gliding path to nanomedicine ranges from the medical use of nanomaterials, to nanoelectronic biosensors, and even possible future applications of molecular nanotechnology. Current problems for nanomedicine involve understanding the issues related to toxicity and environmental impact of nanoparticle materials. Nanomedical approaches to drug delivery center on developing nanoscale particles or molecules to improve the bioavailibility of a drug. Bioavailability refers to the presence of drug molecules where they are needed in the body and where they will do the most good. Infact bioavailibilty is the % fractions of the administered dose which reaches the systemic circulation of the patient. Drug delivery focuses on maximizing bioavailability both at specific places in the body and over a period of time. This will be achieved by molecular targeting by nanoengineered devices. It is all about targeting the molecules and delivering drugs with cell precision. In vivo imaging is another area where tools and devices are being developed. Using nanoparticles contrast agent, images such as ultrasound and MRI have a favorable distribution and improved demarkation. The new methods of nanoengineered materials that are being developed might be effective in treating illnesses and diseases such as cancers & tumors.

Drug delivery systems, lipid- or polymer-based nanoparticles, can be designed to improve the pharmacological and therapeutic properties of drugs. The strength of drug delivery systems is their ability to pharmacokinetics and biodistribution of the drug. It is the size of compartment determines the total amount of drug in the body. Nanoparticles have unusual properties that  can be used to improve drug delivery. The effective actions/pharmacology also depends upon the rate of Administrations of nanomedicines. Where larger particles would have been cleared from the body, cells take up these nanoparticles because of their size. Complex drug delivery mechanisms are being developed, including the ability to get drugs through cell membranes and into cell cytoplasm. Efficiency is important because many diseases depend upon processes within the cell and can only be hindered by drugs that make their  way into the cell. Triggered response (property of nanoparticles )is one way for drug molecules to be used more efficiently. Drugs are placed in the body and only activated on encountering a particular signal. For example, a drug with poor solubility will be replaced by a drug delivery system where both hydrophilic and hydrophobic environments exist, improving the solubility. Also, a drug may cause tissue damage, but with drug delivery, regulated drug release can eliminate the problem. If a drug is cleared too quickly from the body, this could force a patient to use high doses, but with drug delivery systems clearance can be reduced by altering the pharmacokinetics of the drug. Poor biodistribution is a problem that can affect normal tissues through widespread distribution, but the particulates from drug delivery systems lower the volume of distribution and reduce the effect on non-target tissue. Potential nanodrugs will work by very specific and well-understood mechanisms; one of the major impacts of nanotechnology and nanoscience will be in leading development of completely new drugs with more useful behavior and less side effects.

Protein and peptide delivery

Protein and peptides exert multiple biological actions in human body and they have been identified as showing great promise for treatment of various diseases and disorders. These macromolecules are called biopharmaceuticals. Targeted and/or controlled delivery of these biopharmaceuticals using nanomaterials like nanoparticles and Dendrimers is an emerging field called nanobiopharmaceutics, and these products are called nanopharmaceuticals.


WHAT IS DENDRIMERS?

Dendrimers are repeatedly branched molecules. Dendritic molecules are repeatedly-branched species that are characterised by structural perfection. This is based on the evaluation of both symmetry and polydispersity. The field of dendritic molecules can be roughly divided into low-molecular weight and high-molecular weight species. The first category includes dendrimers and dendrons, and the second includes dendronized polymers, hyperbranched polymers and brush-polymers (called also bottle-brushes).


PROPERTIES OF DENDRIMERS

The properties of dendrimers are dominated by the functional groups on the molecular surfaces, however, there are examples of dendrimers with internal functionality. Dendritic encapsulation of functional molecules allows for the isolation of the active site, a structure that mimics the structure of active sites in biomaterials because dendritic scaffolds separate internal and external functions. For example, a dendrimer can be water-soluble when its end group is a hydrophilic group, like a carboxyl group. It is theoretically possible to design a water-soluble dendrimer with internal hydrophobicity, which would allow it to carry a hydrophobic drug in its interior. Recently it has been shown that redox-active nanoparticles can be synthesized, placing the redox molecules between the nanoparticle core and the dendritic wedges; despite their isolation, some of the redox molecules (COOH in this case) remained uncoupled, and thus still reactive.

Another property is that the volume of a dendrimer increases when it has a positive charge. If this property can be applied, dendrimers can be used for drug delivery systems (DDS) that can give medication to the affected part inside a patient’s body directly.

Cancer

It (medical term: malignant neoplasm) is a class of diseases in which a group of cells display uncontrolled growth (cellular division beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood. Most cancers form a tumor but some, like leukemia, do not. Cancer affects people at all ages with the risk for most types increasing with age. Cancer caused about 13% of all human deaths in 2007 (7.6 million).

Cancers are caused by abnormalities in the genetic materials of the transformed cells. These abnormalities may be due to the effects of carcinogens, such as tobacco smoke, radiation, chemicals, or infectious agents. Other cancer-promoting genetic abnormalities may randomly occur through errors in DNA replication, or are inherited, and thus present in all cells from birth. The heritability of cancers is usually affected by complex interactions between carcinogens and the host’s genome……Cancer can be treated by surgery, chemotherapy, radiation therapy, immunology, monoclonal antibody therapy or other methods. The choice of therapy depends upon the location and grade of the tumor and the stage of the disease, as well as the general state of the patient). A number of experimental cancer treatments are also under development.

Complete removal of the cancer without damage to the rest of the body is the goal of treatment. Sometimes this can be accomplished by surgery, but the inclination of cancers to invade adjacent tissue or to spread to distant sites by microscopic metastasis often limits its effectiveness. The effectiveness of chemotherapy is often limited by toxicity to other tissues in the body. Radiation can also cause damage to normal tissue.


PROSPECTS OF NANOMEDICINES

The biological and medical research communities have exploited the unique properties of nanomaterials for various applications (e.g., contrast agents for cell imaging and therapeutics for treating cancer). Terms such as biomedical nanotechnologynanobiotechnology, and nanomedicine are used to describe this hybrid field. Functionalities can be added to nanomaterials by interfacing them with biological molecules or structures. The size of nanomaterials is similar to that of most biological molecules and structures; therefore, nanomaterials can be useful for both in vivo and in vitro biomedical research and applications. Thus far, the integration of nanomaterials with biology has led to the development of diagnostic devices, contrast agents, analytical tools, physical therapy applications, and drug delivery vehicles.

Diagnostics

Nanotechnology-on-a-chip is one more dimension of lab-on-a-chip technology. Magnetic nanoparticles, bound to a suitable antibody, are used to label specific molecules, structures or microorganisms. Gold nanoparticles tagged with short segments of DNA can be used for detection of genetic sequence in a sample. Multicolor optical coding for biological assays has been achieved by embedding different-sized quantum dots into polymeric microbeads. Nanopore technology for analysis of nucleic acids converts strings of nucleotides directly into electronic signatures.

Drug delivery

Nanotechnology has been a boom in medical field by delivering drugs to specific cells using nanoparticles. The overall drug consumption and side-effects can be lowered significantly by depositing the active agent in the morbid region only and in no higher dose than needed. This highly selective approach reduces costs and human suffering. An example can be found in dendrimers and nanoporous materials. Another example is to use block co-polymers, which form micelles for drug encapsulation. They could hold small drug molecules (nanomaolecules) small drug molecules transporting them to the desired location. Another vision is based on small electromechanical systems; NEMS are being investigated for the active release of drugs. Some potentially important applications include cancer treatment with iron nanoparticles or gold shells. A targeted or personalized medicine reduces the drug consumption and treatment expenses resulting in an overall societal benefit by reducing the costs to the public health system. Nanotechnology is also opening up new opportunities in implantable delivery systems, which are often preferable to the use of injectable drugs, because the latter frequently display first-order kinetics (the blood concentration goes up rapidly, but drops exponentially over time). This rapid rise may cause difficulties with toxicity, and drug efficacy can diminish as the drug concentration falls below the targeted range.

Tissue engineering

Nanotechnology can help to reproduce or to repair damaged tissue. “Tissue engineering” makes use of artificially stimulated cell proliferation by using suitable nanomaterial-based scaffolds and growth factors. Tissue engineering might replace today’s conventional treatments like organ transplants or artificial implants. Advanced forms of tissue engineering may lead to life extension.

For patients with end-state organ failure, there may not be enough healthy cells for expansion and transplantation into the ECM (extracellular matrix). In this case, pluripotent stem cells are needed. One potential source for these cells is iPS (induced Pluripontent Stem cells); these are ordinary cells from the patient own body that are reprogrammed into a pluripotent state, and has the advantage of avoiding rejection (and the potentially life-threatening complications associated with immunosuppressive treatments). Another potential source of pluripotent cells is from embryos, but this has two disadvantages:

1) It requires that we solve the problem of cloning, which is technically very difficult (especially preventing abnormalities).

2) It requires the harvesting of embryos. Given that each one of us was once an embryo, this source is claimed by some to be ethically problematic.

Bottom-up approaches

  • These seek to arrange smaller components into more complex assemblies.

DNA nanotechnology utilizes the specificity of Watson-Crick base pairing to construct well defined structures out of DNA and other nucleic acids.

Image of a DNA biochip elaborated by bottom-up approach.

  • Approaches from the field of “classical” chemical synthesis also aim at designing molecules with well-defined shape (e.g. bis-peptides).
  • More generally, molecular self assembly seek to use concepts of supramolecular chemistry, and molecular recognition in particular, to cause single-molecule components to automatically arrange themselves into some useful conformation.



Chemistry and environment

Chemical catalysis and filtration techniques are two prominent examples where nanotechnology already plays a role. The synthesis provides novel materials with tailored features and chemical properties: for example, nanoparticles with a distinct chemical surrounding (ligands), or specific optical properties. In this sense, chemistry is indeed a basic nanoscience. In a short-term perspective, chemistry will provide novel “nanomaterials” and in the long run, superior processes such as “self-assembly” will enable energy and time preserving strategies. In a sense, all chemical synthesis can be understood in terms of nanotechnology, because of its ability to manufacture certain molecules. Thus, chemistry forms a base for nanotechnology providing tailor-made molecules, polymers as well as clusters and nanoparticles.


The small size of nanoparticles endows them with properties that can be very useful in oncology, particularly in imaging. Quantum dots (nanoparticles with quantum confinement properties, such as size-tunable light emission), when used in conjunction with MRI (magnetic resonance imaging), can produce exceptional images of tumor sites. These nanoparticles are much brighter than organic dyes and only need one light source for excitation. This means that the use of fluorescent quantum dots could produce a higher contrast image and at a lower cost than today’s organic dyes used as contrast media. The downside, however, is that quantum dots are usually made of quite toxic elements.

Another nanoproperty, high surface area to volume ratio, allows many functional groups to be attached to a nanoparticle, which can seek out and bind to certain tumor cells. Additionally, the small size of nanoparticles (10 to 100 nanometers), allows them to preferentially accumulate at tumor sites (because tumors lack an effective lymphatic drainage system). A very exciting research question is how to make these imaging nanoparticles more activating to cure cancer upto maximum extent. For illustration, is it possible to design the multifunctional nanoparticles that would detect, image, and then proceed to treat/cure a tumor growth (cancer)? This question is still under energetic investigation; the answer to which could architect the future of cancer treatment. A promising new cancer treatment that may one day replace radiation and chemotherapy is edging closer to human trials. Kanzius RF therapy attaches microscopic nanoparticles to cancer cells and then “cooks” tumors inside the body with radio waves that heat only the nanoparticles and the adjacent (cancerous) cells.

Kanzius RF Therapy –A milestone in Nanomedical Science

Kanzius RF Therapy is an experimental cancer treatment that employs a combination of either gold or carbon nano carbon particles and radio waves to heat and destroy cancer cells without damaging healthy cells.

The specific absorption rate for radio waves by living tissue in the proposed wavelengths and intensity levels is very low. Metals absorb this energy much more efficiently than tissue through dielectric heating ; carbon nanotubes could be used to similar purpose of nanoparticles were to be preferentially bound to cancer sites, cancer cells could be destroyed or induced into apoptosis while leaving healthy tissue relatively unharmed. It is preferential targeting represents a major technical challenge.


(This device transfers energy from nano-thin layers of quantum wells to nanocrystals above them, causing the nanocrystals to emit visible light).

Kenzius built a prototype in his home,  Kanzius RF device  and formed Therm Med., LLC to test and market his inventions. The device was successfully tested at University of Pittsburgh Medical Center in 2005.

Sensor test chips containing thousands of nanowires, able to detect proteins and other biomarkers left behind by cancer cells, could enable the detection and diagnosis of cancer in the early stages from a few drops of a patient’s blood.

The basic point to use drug delivery is based upon three facts:

a) efficient encapsulation of the drugs,

b) successful delivery of said drugs to the targeted region of the body, and

c) successful release of that drug there.

Besides this the factors governing the Pharmacokinetics of drug are BIOAVAILIBILITY, DOSAGE FORM, CHEMICAL FORM, ADMINISTRATION RATE, DESIRED PLASMA CONCENTRATIONS, VOLUME OF DISTRIBUTION, LOADING DOSE, CLEARANCE

Researchers have demonstrated the use of 120 nm diameter nanoshells coated with gold or carbon nanoparticles to kill cancer tumors in mice. The nanoshells can be targeted to bond to cancerous cells by conjugating antibodies to the nanoshell surface. By irradiating the area of the tumor with an infrared laser, which passes through flesh without heating it, the gold is heated sufficiently to cause death to the cancer cells. ( as by Kanzius RF therapy)

Additionally, John Kanzius has invented a radio machine which uses a combination of radio waves and carbon or gold nanoparticles to destroy cancer cells.

Nanoparticles of cadmium selenide(quantum dots) glow when exposed to ultraviolet light. When injected, they seep into cancer tumors. The surgeon can see the glowing tumor, and use it as a guide for more accurate tumor removal.

In photodynamic therapy, a particle is placed within the body and is illuminated with light from the outside. The light gets absorbed by the particle and if the particle is metal, energy from the light will heat the particle and surrounding tissue. Light may also be used to produce high energy oxygen molecules which will chemically react with and destroy most organic molecules that are next to them (like tumors). This therapy is appealing for many reasons. It does not leave a “toxic trail” of reactive molecules throughout the body (chemotherapy) because it is directed where only the light is shined and the particles exist. Photodynamic therapy has potential for a noninvasive procedure for dealing with diseases, growths, and tumors.

Visualization

Tracking movement can help determine how well drugs are being distributed or how substances are metabolized. It is difficult to track a small group of cells throughout the body, so scientists used to dye the cells. These dyes needed to be excited by light of a certain wavelength in order for them to light up. While different color dyes absorb different frequencies of light, there was a need for as many light sources as cells. A way around this problem is with luminescent tags. These tags are quantum m dots attached to proteins that penetrate cell membranes. The dots can be random in size, can be made of bio-inert material, and they demonstrate the nanoscale property that color is size-dependent. As a result, sizes are selected so that the frequency of light used to make a group of quantum dots fluoresce is an even multiple of the frequency required to make another group incandesce. Then both groups can be lit with a single light source.

Nanoparticle targeting

It is greatly observed that nanoparticles are promising tools for the advancement of drug delivery, medical imaging, , and as diagnostic sensors. However, the biodistribution of these nanoparticles is mostly unknown due to the difficulty in targeting specific organs in the body. Current research in the excretory systems of mice, however, shows the ability of gold composites to selectively target certain organs based on their size and charge. These composites are encapsulated by a dendrimer and assigned a specific charge and size. Positively-charged gold nanoparticles were found to enter the kidneys while negatively-charged gold nanoparticles remained in the liver and spleen. Even at a relatively small size of 5 nm , these particles can become compartmentalized in the peripheral tissues, and will therefore accumulate in the body over time. While advancement of research proves that targeting and distribution can be augmented by nanoparticles, the dangers of nanotoxicity become an important next step in further understanding of their medical uses.


Portals & Scope by Neuro-electronics

Neuro-electronic interfacing is a visionary goal dealing with the construction of nanodevices that will permit computers to be joined and linked to the nervous system. This idea requires the building of a molecular structure that will permit control and detection of nerve impulses by an external computer. The computers will be able to interpret, register, and respond to signals the body gives off when it feels sensations. The demand for such structures is huge because many diseases involve the decay of the nervous systems. Also, many injuries and accidents may impair the nervous system resulting in dysfunctional systems and paraplegia. If computers could control the nervous system through neuro-electronic interface, problems that impair the system could be controlled so that effects of diseases and injuries could be overcome. Two considerations must be made when selecting the power source for such applications. They are renewable and nonrenewable strategies. A renewable strategy implies energy is refilled continuously or periodically with external sonic, chemical, magnetic, or electrical sources. A nonrenewable strategy implies that all power is drawn from internal energy storage which would stop when all energy is drained.

One limitation to this innovation is the fact that electrical interference is a possibility. Electric fields, electromagnetic pulses (EMP), and stray fields from other in vivo electrical devices can all cause interference. Also, thick insulators are required to prevent electron leakage, and if high conductivity of the in vivo medium occurs there is a risk of sudden power loss and “shorting out.” Finally, thick wires are also needed to conduct substantial power levels without overheating. Little practical progress has been made even though research is happening. The wiring of the structure is extremely difficult because they must be positioned precisely in the nervous system so that it is able to monitor and respond to nervous signals. The structures that will provide the interface must also be compatible with the body’s immune system so that they will remain unaffected in the body for a long time. In addition, the structures must also sense ionic currents and be able to cause currents to flow backward. The structural design of these devices are amazing & a challenge for the new Science era……….

Medical applications of molecular nanotechnology

Molecular nanotechnology is a speculative subfield of nanotechnology regarding the possibility of engineering molecular assemblers, , machines which could re-order matter at a molecular or atomic scale. Molecular nanotechnology is highly theoretical, seeking to anticipate what inventions nanotechnology might yield and to propose an agenda for future inquiry. The proposed elements of molecular nanotechnology, such as molecular assemblers and nanorobots are far beyond current capabilities.

Nanorobots

The somewhat speculative claims about the possibility of using nanorobots in medicine, advocates say, would totally change the world of medicine once it is realized. Nanomedicine would make use of these nanorobots, introduced into the body, to repair or detect damages and infections. According toRobert Freitas of the Institute for Molecular Manufacturing, a typical blood borne medical nanorobot would be between 0.5-3 micrometres in size, because that is the maximum size possible due to capillary passage requirement. Carbon could be the primary element used to build these nanorobots due to the inherent strength and other characteristics of some forms of carbon (diamond/fullerene composites), and nanorobots would be fabricated in desktop nanofactories specialized for this purpose.

Nanodevices could be observed at work inside the body using MRI, especially if their components were manufactured using mostly 13C atoms rather than the natural 12C isotope of carbon, since 13C has a nonzero nuclear magnetic moment. Medical nanodevices would first be injected into a human body, and would then go to work in a specific organ or tissue mass. The doctor will monitor the progress, and make certain that the nanodevices have gotten to the correct target treatment region. The doctor will also be able to scan a section of the body, and actually see the nanodevices congregated neatly around their target (a tumor mass, etc.) so that he or she can be sure that the procedure was successful.

Cell repair machines

Using drugs and surgery, doctors can only encourage tissues to repair themselves. With molecular machines, there will be more direct repairs. Cell repair will utilize the same tasks that living systems already prove possible. Access to cells is possible because biologists can stick needles into cells without killing them. Thus, molecular machines are capable of entering the cell. Also, all specific biochemical interactions show that molecular systems can recognize other molecules by touch, build or rebuild every molecule in a cell, and can disassemble damaged molecules. Finally, cells that replicate prove that molecular systems can assemble every system found in a cell. Therefore, since nature has demonstrated the basic operations needed to perform molecular-level cell repair, in the future, nanomachine based systems will be built that are able to enter cells, sense differences from healthy ones and make modifications to the structure.

The possibilities of these cell repair machines are impressive. Comparable to the size of viruses or bacteria, their compact parts would allow them to be more complex. The early machines will be specialized. As they open and close cell membranes or travel through tissue and enter cells and viruses, machines will only be able to correct a single molecular disorder like DNA damage or enzyme deficiency. Later, cell repair machines will be programmed with more abilities with the help of advanced AI systems.

Nanocomputers will be needed to guide these machines. These computers will direct machines to examine, take apart, and rebuild damaged molecular structures. Repair machines will be able to repair whole cells by working structure by structure. Then by working cell by cell and tissue by tissue, whole organs can be repaired. Finally, by working organ by organ, health is restored to the body. Cells damaged to the point of inactivity can be repaired because of the ability of molecular machines to build cells from scratch. Therefore, cell repair machines will free medicine from reliance on self repair alone.

Nanonephrology

Nanonephrology is a branch of nanomedicine and nanotechnology that deals with 1) the study of kidney protein structures at the atomic level; 2) nano-imaging approaches to study cellular processes in kidney cells; and 3) nano medical treatments that utilize nanoparticles and to treat various kidney diseases. The creation and use of materials and devices at the molecular and atomic levels that can be used for the diagnosis and therapy of renal diseases is also a part of Nanonephrology that will play a role in the management of patients with kidney disease in the future. Advances in Nanonephrology will be based on discoveries in the above areas that can provide nano-scale information on the cellular molecular machinery involved in normal kidney processes and in pathological states. By understanding the physical and chemical properties of proteins and other macromolecules at the atomic level in various cells in the kidney, novel therapeutic approaches can be designed to combat major renal diseases. The nano-scale artificial kidney is a goal that many physicians dream of. Nano-scale engineering advances will permit programmable and controllable nano-scale robots to execute curative and reconstructive procedures in the human kidney at the cellular and molecular levels. Designing nanostructures compatible with the kidney cells and that can safely operate in vivo is also a future goal. The ability to direct events in a controlled fashion at the cellular nano-level has the potential of significantly improving the lives of patients with kidney diseases.


The Future ARENA of Nanotechnology

Nanotechnology is already found in minute particles used in everyday products such as in sunscreens. Many sunscreens today contain zinc oxide or titanium oxide nanoparticles that allow the creams to be absorbed into the skin, leaving no whitish residue behind. Nanoparticles are also used in scratch-resistant glass, wrinkle-resistant clothes, and stronger but lighter tennis rackets

However, these are “pedestrian applications” of a very powerful science. It is in the medical arena that the really interesting work is happening. For example, nanoscale magnets might be used to improve the contrast between healthy and diseased tissue in medical resonance imaging. Clinical trials in the U.S. testing to see if nanoparticles can be used to kill cancerous cells in humans have shown promising results.

The next five to 10 years will see a lot of interesting work being done in the medical area. It is in the next 10-15 years that we will see truly “transformational changes”. For example, materials that might detect toxins in clothes would be a strong possibility.

 

 

 

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October 29, 2010

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