Nanotechnology in medicine: Part 2
Nanoparticles: delivery to the address
Anna Petrenko, Copper NewsIn the first part of the review of "Copper News" on nanoparticles, it was about the history of their introduction in medicine and the basic principles of use.
In the second part, we will talk about overcoming the blood-brain barrier, metal nanoparticles and the problem of toxicity.
Seeping through barriersAn important property of nanoparticles is the ability to carry medicine through the blood–brain barrier.
Special selective transporters in the BBB supply glucose, free fatty acids, amino acids, vitamins, minerals and electrolytes to the brain.
But for almost all large and more than 98% of low-mass molecules, the entrance is closed: dense contacts between brain endotheliocytes and their biochemical properties do not allow substances from the general bloodstream to penetrate. Most drugs either cannot get to the target, or the concentration of molecules that have crossed the border turns out to be very small compared to the one introduced into the body. In this case, it is necessary to give a person doses of medicine much larger than necessary for treatment. And this can cause side effects in other organs.
The mechanism of drug delivery through the BBB has long remained a mystery and has not yet been fully clarified.
The two main ways in which delivery is carried out are increasing the concentration of the drug in or near the lumen of the BBB, or passing along with the molecule directly to the brain (you can read more about this in the articles in Current Medicinal Chemistry and Drug Development and Industrial Pharmacy).
Now the need for targeted delivery is very high. Diseases, the sources of which are localized in the brain, are becoming more common, mortality from them is higher, and their social significance is increasing. There is simply no treatment for many of them: for example, for amyotrophic lateral sclerosis, prion diseases, Alzheimer's, Parkinson's, Huntington's.
For other neurological diseases, therapy exists, but it needs improvement. The appearance in clinical practice of nanoparticles delivering drugs through the BBB could significantly improve the therapy of epilepsy, multiple sclerosis, migraines, traumatic brain injuries, diseases of cerebral vessels, neuroinfections, and some types of brain tumors.
Nanoeedles passing through the blood-brain barrier. Photo: Wellcome Images / Flickr
Nano-successes from RussiaThe idea of intravenous injections of nanoparticles to get into the brain was born by Professor Peter Paul Speiser, head of the laboratory in Zurich, around 1980.However, Jorg Kreuter recalls that he himself considered it a "stupid idea": he thought that the BBB would be forever impervious to nanoscientific progress. He heard this idea again twelve years later from the Moscow scientist Renad Alyautdin. In a Russian laboratory, he showed on an animal model that a special form of nanoparticles – coated with polysorbate 80 – associated with various drugs (dalargin hexapeptide, loperamide or tubocurarin) works. There was no effect from the drugs in free form.Later, other Russian scientists, Svetlana Gelperina and her group, showed that nanoparticles with doxorubicin (a cytostatic used in cancer chemotherapy), coated with polysorbate 80, extremely effectively deliver the drug to the brain.
Now scientists are actively developing various designs that can carry the drug through the BBB. For example, in a mouse model, gold nanoparticles targeted at the insulin receptor in the brain were tested. After injection into the caudal vein, they penetrated into the brain through receptor-mediated endocytosis. In the experimental group, compared with the control, which was injected with ordinary gold nanoparticles, two hours after the injection, there were five times more such nanoparticles.
Types of gold nanoparticles. Photo: University of Southampton
There are also workarounds to the brain, which are also being investigated by scientists. For example, brain neurotrophic factor (BDNF) can be used as therapy for neurodegenerative disorders, including hearing and vision loss. But it is not easy to get to the retina and inner ear: there are hemato-retinal and hemato-labyrinth barriers similar to BBB. Instillation of the drug conjugated with nanoparticles allows BDNF to penetrate to the cochlea or the back of the eye. This, as the authors of the experiment write, can lead to long-term or even complete prevention of degeneration of auditory and visual neurons.
Metals are noble and not veryThe gold nanoparticles to the insulin receptor described above are far from the only metal "tool" of this technology.
The materials used are gold, silver, iron, zinc and titanium. They have unique physical and chemical properties. For example, photoluminescence and superparamagnetic properties of metal nanoparticles are used for visualization, and the ability to produce reactive oxygen species (ROS) and heating with photothermal effect are used to destroy cancer cells.
The laboratory of Steve Fiering at the Norris Cotton Cancer Center has shown that it is possible not only to cause a local temperature increase by exposure to electromagnetic energy, infrared radiation or radio waves on individual nanoparticles, but also thereby provoke an immune response to a tumor.
In addition, metal nanoparticles are biocompatible with the body and are easily removed from it.
Often metal nanoparticles are coated on top with a thin layer of polymer and conjugated with the drug. For example, the first gold nanoparticles with a polymer shell were made in 2008. Such a complex design is multifunctional and extremely effective. But researchers were tormented by the question of why gold nanoparticles so easily penetrate through the cell membrane – after all, it would seem that it reliably shields the cell from unwanted influences.
Researchers from the Massachusetts Institute of Technology (MIT) and the Ecole Polytechnique de Lausanne (Ecole Polytechnique de Lausanne) in Switzerland have shown that nanoparticles first mix with membrane lipids and so penetrate into the cell.
The work of an international team of researchers has just been published, in which they managed to analyze the stability of gold nanoparticles coated with polymer and track their distribution in the body. To do this, they labeled the nanoparticles with radioactive isotopes. Interesting results were obtained: it turned out that even conjugated highly stable nanoparticles can behave differently in person than in vitro. In this case, for example, the shell separated from the nanoparticle under the action of liver enzymes.
The latest developments of scientists are not only related to gold. The antibacterial and anti-inflammatory properties of silver are also used in therapy. Its ions are highly toxic to microorganisms, but researchers have not yet come to a consensus on the exact mechanism of such an effect.
They are also used as antitumor therapy. In 2014, a team from the University of California at Santa Barbara (UC Santa Barbara) developed unique spherical silver nanoparticles coated with peptides that target cancer cells. The shell of nanoparticles that have not found a "target" is destroyed and does not interfere with subsequent visualization.
Scientists from Houston Methodist Hospital (Houston Methodist) this year developed a form of nanoparticles that destroy blood clots 100-1000 times faster than the techniques usually used for this. Nanoparticles made of iron oxide coated with albumin, a blood protein that "hides" nanoparticles from the immune system and gives time to reach a blood clot. Iron oxide can subsequently be used for MRI scanning, manipulation of external magnetic fields and subsequent calming of thrombus destruction by local heating.
The drug loaded into nanoparticles is a molecule of tissue plasminogen activator (TAP, tPA). This enzyme is contained in small concentrations in the blood, and it is usually administered in difficult situations to patients with suspected blood clots. However, the usual inappropriate administration of TAP can be dangerous with hemorrhages.
The experiments were carried out on a mouse model and on human blood. If the development is successful, it will help prevent many consequences of blood clots: strokes, heart attacks, pulmonary embolism and others. Next, the team of scientists plans to conduct experiments on the use of these nanoparticles in external magnetic fields: to guide and heat the nanoparticles.
A fly in the ointmentJust as the magic bullet exists only in operas, so ideal medicines have not yet been invented.
The "fly in the ointment" for nanotechnology – toxicological risks.
The nanotechnology industry is developing rapidly, but the impact of nanoparticles on humans and the environment is studied very little. A more thorough approach is observed only in biomedicine.
As shown in animal models, the material of nanoparticles becomes more toxic when inhaled than the same material, but in larger particles. In the lungs of animals, the researchers recorded a strong inflammatory reaction, especially from carbon nanotubes. When ingested orally or inhaled, nanoparticles are rapidly absorbed into the blood, spread to organs and tissues, and in some cases even cause platelet aggregation and vascular thrombosis in the carotid arteries of rats.
According to research by Russian scientists from the Faculty of Biology of Moscow State University, from the Koltsov Institute of Developmental Biology, the Frumkin Institute of Physical Chemistry and Electrochemistry of the Russian Academy of Sciences and the Engelhardt Institute of Molecular Biology, gold nanoparticles can suppress processes important for fertilization of an egg by a sperm. "To put it crudely and figuratively, gilded spermatozoa are bad lovers," comments one of the authors of the study, biologist Sabir Zahidov.
There are also new models for testing the toxicity of drugs. "Nanoparticles in general are new materials, and we don't know much about their impact on human health and the state of the ecosystem," commented Qilin Li, head of the project using C. elegans roundworms. Scientists tested 20 types of nanoparticles on nematodes. Based on the reaction of worms, for example, on mobility, growth and life expectancy, the group found that five drugs are practically non–toxic.
Portal "Eternal youth" http://vechnayamolodost.ru
01.07.2015