A pardonable deception
By deceiving the immune system, it is possible to prolong the work of therapeutic nanoparticles
Scientists of the Moscow Institute of Physics and Technology, together with colleagues from the M. M. Shemyakin and Yu. A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences and the A. M. Prokhorov Institute of General Physics of the Russian Academy of Sciences, have developed a technology that can significantly increase the circulation time in the blood of almost any biomedical nanomaterials, increasing their therapeutic effectiveness. The work was published in the journal Nature Biomedical Engineering (Nikitin et al., Enhancement of the blood-circulation time and performance of nanomedicines via the forced clearance of erythrocytes).
The widespread use of therapeutic nanoparticles is hindered by the effective functioning of the human immune system. Over a long period of evolution, the body has learned to fight very well with foreign nanomaterials – be it viruses or smoke particles. Therefore, when reasonable doses of most artificially created nanoparticles are injected into the bloodstream, the cells of the immune system absorb them in a matter of minutes or even tens of seconds.
Scientists led by Maxim Nikitin, Head of the Laboratory of Nanobiotechnology at MIPT, have proposed an innovative technology that can significantly extend the circulation time and increase the therapeutic activity of various nanoagents. They took advantage of the fact that the immune system continuously removes "aged" red blood cells from the bloodstream – about 1% of red blood cells per day in humans.
"We assumed that if we force the body to slightly strengthen this natural process, then the immune system can "get carried away" by removing red blood cells and will pay less attention to therapeutic nanoparticles. Moreover, we wanted to outwit the immune system as gently as possible, ideally by means of the body itself, and not artificially synthesized substances," says Maxim Nikitin.
To do this, scientists injected mice with antibodies that specifically bind to red blood cells. A small dose of antibodies (1.25 mg/kg) made it possible to achieve a tenfold prolongation of the circulation of nanoparticles in the bloodstream. At the same time, the antibodies caused only mild anemia – a drop in hematocrit (the number of red blood cells in the blood) by 5%.
Researchers have shown that this approach, called the cytoblocade of the mononuclear phagocytic system, is universal from the point of view of nanoparticles. It prolongs the circulation of small quantum dots of 8 nanometers in size, and 100-nanometer particles, and large micron particles, and even the most advanced nanoagents approved for the introduction of stealth liposomes to humans (agents with a polymer coating that masks them from the immune system). At the same time, the cytoblocade does not reduce the body's ability to fight bacteria entering the bloodstream (which are also microparticles), both in conditions of a small dose of bacteria and in conditions of sepsis.
Scientists have demonstrated the effectiveness of the method for oncotherapy. The cytoblocade significantly (up to 23 times) improved the magnetically mediated delivery of nanoparticles to the tumor. This method uses a magnetic field for additional focusing and retention of magnetic medicinal agents in the tumor, thereby reducing systemic toxicity. In addition, the developed method made it possible to carry out effective therapy of melanoma with the help of liposomes loaded with magnetite and doxorubicin, which were completely inoperable without the introduction of anti-erythrocyte antibodies. Improved magnetic delivery has been demonstrated for five types of tumors of different natures: from melanoma to breast cancer.
The authors note that the increase in the efficiency of particles in the body clearly correlated with the prolongation of their circulation in the bloodstream. This correlation was confirmed thanks to the scientists' own unique development, namely, the highly sensitive method for registering magnetic particles MPQ (magnetic particle quantification). It allows you to register the kinetics of the removal of particles from the bloodstream without taking blood.
"Of course, the combined effect of existing or new anti-erythrocyte antibodies with antitumor and other drugs should be thoroughly tested by clinical trials. However, we are extremely optimistic about this technology and its application for the treatment of serious diseases where targeted drug delivery is required, including cancer. Now that the publication stage of this complex seven-year study has been completed, we simply have to make every possible effort to translate this technology into global clinical practice. Therefore, in particular, we are very much looking for active colleagues who want to join our team, as well as collaborators," says Maxim Nikitin.
Portal "Eternal youth" http://vechnayamolodost.ru