Nanomedicine

Nanomedicine is the medical application of nanotechnology.^[1] Nanomedicine ranges from the medical applications of nanomaterials and biological devices, to nanoelectronic biosensors, and even possible future applications of molecular nanotechnology such as biological machines. Current problems for nanomedicine involve understanding the issues related to toxicity and environmental impact of nanoscale materials (materials whose structure is on the scale of nanometers, i.e. billionths of a meter).

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.

Nanomedicine seeks to deliver a valuable set of research tools and clinically useful devices in the near future.^[2][3] The National Nanotechnology Initiative expects new commercial applications in the pharmaceutical industry that may include advanced drug delivery systems, new therapies, and in vivo imaging.^[4] Nanomedicine research is receiving funding from the US National Institutes of Health, including the funding in 2005 of a five-year plan to set up four nanomedicine centers.

Nanomedicine is a large industry, with nanomedicine sales reaching $6.8 billion in 2004, and with over 200 companies and 38 products worldwide, a minimum of $3.8 billion in nanotechnology R&D is being invested every year.^[5] In April 2006, the journal Nature Materials estimated that 130 nanotech-based drugs and delivery systems were being developed worldwide.^[6] As the nanomedicine industry continues to grow, it is expected to have a significant impact on the economy.

Drug delivery

Nanoparticles (top), liposomes (middle), and dendrimers (bottom) are some nanomaterials being investigated for use in nanomedicine.

The overall drug consumption and side-effects may be lowered significantly by depositing the active agent in the morbid region only and in no higher dose than needed. Targeted drug delivery is intended to reduce the side effects of drugs with concomitant decreases in consumption and treatment expenses. Drug delivery focuses on maximizing bioavailability both at specific places in the body and over a period of time. This can potentially be achieved by molecular targeting by nanoengineered devices.^[7][8] More than $65 billion are wasted each year due to poor bioavailability. A benefit of using nanoscale for medical technologies is that smaller devices are less invasive and can possibly be implanted inside the body, plus biochemical reaction times are much shorter. These devices are faster and more sensitive than typical drug delivery.^[9] The efficacy of drug delivery through nanomedicine is largely based upon: a) efficient encapsulation of the drugs, b) successful delivery of drug to the targeted region of the body, and c) successful release of the drug.

Drug delivery systems, lipid- ^[10] or polymer-based nanoparticles,^[11] can be designed to improve the [18]

Nanoparticles can be used in combination therapy for decreasing antibiotic resistance or for their antimicrobial properties.^[19][20][21] Nanoparticles might also used to circumvent multidrug resistance (MDR) mechanisms.^[22]

Types of systems used

Two forms of nanomedicine that have already been tested in mice and are awaiting human trials that will be using gold nanoshells to help diagnose and treat cancer,^[23] and using liposomes as vaccine adjuvants and as vehicles for drug transport.^[24][25] Similarly, drug detoxification is also another application for nanomedicine which has shown promising results in rats.^[26] Advances in Lipid nanotechnology was also instrumental in engineering medical nanodevices and novel drug delivery systems as well as in developing sensing applications.^[27] Another example can be found in dendrimers and nanoporous materials. Another example is to use block co-polymers, which form micelles for drug encapsulation.^[11]

Polymeric nano-particles are a competing technology to lipidic (based mainly on Phospholipids) nano-particles. There is an additional risk of toxicity associated with polymers not widely studied or understood. The major advantages of polymers is stability, lower cost and predictable characterisation. However, in the patient's body this very stability (slow degradation) is a negative factor. Phospholipids on the other hand are membrane lipids (already present in the body and surrounding each cell), have a GRAS (Generally Recognised As Safe) status from FDA and are derived from natural sources without any complex chemistry involved. They are not metabolised but rather absorbed by the body and the degradation products are themselves nutrients (fats or micronutrients).

Protein and peptides exert multiple biological actions in the 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 nanobiopharmaceuticals.

Another vision is based on small electromechanical systems; nanoelectromechanical systems are being investigated for the active release of drugs. Some potentially important applications include cancer treatment with iron nanoparticles or gold shells.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.

Applications

Some nanotechnology-based drugs that are commercially available or in human clinical trials include:

• Abraxane, approved by the U.S. Food and Drug Administration (FDA) to treat breast cancer,^[28] non-small- cell lung cancer (NSCLC)^[29] and pancreatic cancer,^[30] is the nanoparticle albumin bound paclitaxel.
• Doxil was originally approved by the FDA for the use on HIV-related Kaposi's sarcoma. It is now being used to also treat ovarian cancer and multiple myeloma. The drug is encased in liposomes, which helps to extend the life of the drug that is being distributed. Liposomes are self-assembling, spherical, closed colloidal structures that are composed of lipid bilayers that surround an aqueous space. The liposomes also help to increase the functionality and it helps to decrease the damage that the drug does to the heart muscles specifically.^[31]
• Onivyde, liposome encapsulated irinotecan to treat metastatic pancreatic cancer, was approved by FDA on October 2015. ^[32]
• C-dots (Cornell dots) are the smallest silica-based nanoparticles with the size <10 nm. The particles are infused with organic dye which will light up with fluorescence. Clinical trial is underway since 2011 to use the C-dots as diagnostic tool to assist surgeons to identify the location of tumor cells.^[33]
• An early phase clinical trial using the platform of ‘Minicell’ nanoparticle for drug delivery have been tested on patients with advanced and untreatable cancer. Built from the membranes of mutant bacteria, the minicells were loaded with nanometers, the minicell is bigger than synthetic particles developed for drug delivery. The researchers indicated that this larger size gives the minicells a better profile in side-effects because the minicells will preferentially leak out of the porous blood vessels around the tumor cells and do not reach the liver, digestive system and skin. This Phase 1 clinical trial demonstrated that this treatment is well tolerated by the patients. As a platform technology, the minicell drug delivery system can be used to treat a number of different cancers with different anti-cancer drugs with the benefit of lower dose and less side-effects.^[34][35]
• In 2014, a Phase 3 clinical trial for treating inflammation and pain after cataract surgery, and a Phase 2 trial for treating dry eye disease were initiated using nanoparticle loteprednol etabonate.^[36] In 2015, the product, KPI-121 was found to produce statistically significant positive results for the post-surgery treatment.^[37]

Cancer

A schematic illustration showing how nanoparticles or other cancer drugs might be used to treat cancer.

Existing and potential drug nanocarriers have been reviewed.^{[38][39][40][41]}

Nanoparticles have high surface area to volume ratio. This allows for 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).^[42] Limitations to conventional cancer chemotherapy include drug resistance, lack of selectivity, and lack of solubility. Nanoparticles have the potential to overcome these problems.^[43]

In [59]^[60] Potentially, these nanocomposites may be used as a novel, mechanically strong, light weight composite as bone implants.

For example, a flesh welder was demonstrated to fuse two pieces of chicken meat into a single piece using a suspension of gold-coated nanoshells activated by an infrared laser. This could be used to weld arteries during surgery.^[61] Another example is nanonephrology, the use of nanomedicine on the kidney.

Medical devices

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. A refuelable strategy implies energy is refilled continuously or periodically with external sonic, chemical, tethered, magnetic, or biological electrical sources, while a nonrefuelable strategy implies that all power is drawn from internal energy storage which would stop when all energy is drained. A nanoscale enzymatic biofuel cell for self-powered nanodevices have been developed that uses glucose from biofluids including human blood and watermelons.^[62] One limitation to this innovation is the fact that electrical interference or leakage or overheating from power consumption is possible. The wiring of the structure is extremely difficult because they must be positioned precisely in the nervous system. The structures that will provide the interface must also be compatible with the body's immune system.^[63]

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. Nanomedicine would make use of these nanorobots, introduced into the body, to repair or detect damages and infections. 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.^{[1][63][64][65]}

See also

References

Further reading

Tissue engineering

This approach offers new therapeutic possibilities for the treatment of systemic infections such as sepsis by directly removing the pathogen. It can also be used to selectively remove cytokines or endotoxins^[53] or for the dialysis of compounds which are not accessible by traditional dialysis methods. However the technology is still in a preclinical phase and first clinical trials are not expected before 2017.^[58]

The small size (< 100 nm) and large surface area of functionalized nanomagnets leads to advantageous properties compared to hemoperfusion, which is a clinically used technique for the purification of blood and is based on surface adsorption. These advantages are high loading and accessibility of the binding agents, high selectivity towards the target compound, fast diffusion, small hydrodynamic resistance, and low dosage.^[57]

The purification process is based on functionalized iron oxide or carbon coated metal nanoparticles with ferromagnetic or superparamagnetic properties.^[52] Binding agents such as proteins,^[51] antibodies,^[50] antibiotics,^[53] or synthetic ligands^[54] are covalently linked to the particle surface. These binding agents are able to interact with target species forming an agglomerate. Applying an external magnetic field gradient allows exerting a force on the nanoparticles. Hence the particles can be separated from the bulk fluid, thereby cleaning it from the contaminants.^[55][56]

Magnetic micro particles are proven research instruments for the separation of cells and proteins from complex media. The technology is available under the name Magnetic-activated cell sorting or Dynabeads among others. More recently it was shown in animal models that magnetic nanoparticles can be used for the removal of various noxious compounds including toxins, pathogens, and proteins from whole blood in an extracorporeal circuit similar to dialysis.^[50][51] In contrast to dialysis, which works on the principle of the size related diffusion of solutes and ultrafiltration of fluid across a semi-permeable membrane, the purification with nanoparticles allows specific targeting of substances. Additionally larger compounds which are commonly not dialyzable can be removed.

Blood purification

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.^[48] Nanotechnology is helping to advance the use of arthroscopes, which are pencil-sized devices that are used in surgeries with lights and cameras so surgeons can do the surgeries with smaller incisions. The smaller the incisions the faster the healing time which is better for the patients. It is also helping to find a way to make an arthroscope smaller than a strand of hair.^[49]

Sensing

[47] 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

The small size of nanoparticles endows them with properties that can be very useful in contrast media. The downside, however, is that quantum dots are usually made of quite toxic elements.

In vivo imaging is another area where tools and devices are being developed. Using nanoparticle contrast agents, images such as ultrasound and MRI have a favorable distribution and improved contrast. This might be accomplished by self assembled biocompatible nanodevices that will detect, evaluate, treat and report to the clinical doctor automatically.

Visualization

^[45][44]