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The new solution prolongs blood circulation for virtually any nanomedicine, boosting its therapeutic efficiency. The development of medical chemistry since the late 19th century has led to the transition from traditional medicine to drugs with strictly defined chemical formulas. Despite being some 150 years old, this paradigm still underlies the absolute majority of modern medications. Their active molecules tend to perform one simple function: activate or deactivate a certain receptor.
However, since the 1970s, many laboratories have been pursuing next-generation drugs that would implement multiple complex actions simultaneously, for example, identifying cancer cells via a range of biochemical cues, signaling the tumor location to the physician, and subsequently destroying all the malignant cells via toxins and heating.
Since one molecule cannot perform all of these functions, a larger supramolecular structure, or a nanoparticle, is required. However, despite the enormous variety of nanomaterials developed to date, only the simplest ones with highly specific functions have made it into clinical practice. The main problem in using therapeutic nanoparticles has to do with the amazing efficiency of the immune system. Over millennia, evolution has perfected the human body's ability to eliminate nanosized foreign entities, from viruses to smoke particles.
When administered in reasonable doses, most artificial nanoparticles are cleared from the bloodstream by the immune system in mere minutes or even seconds. That means no matter how sophisticated the drugs are, the majority of the dose will not even have a chance to come in contact with the target, but will affect healthy tissues, usually in a toxic way.
In their recent paper, a team of Russian researchers
proposed a groundbreaking universal technology that significantly prolongs the blood circulation and enhances the therapeutic efficiency of diverse nanoagents without necessitating their modification.
The technology exploits the fact that the immune system continually eliminates the old, "expired" red blood cells—about 1% per day in humans—from the bloodstream. They hypothesized that if they slightly intensified this natural process, tehy could trick the immune system. While it becomes busy clearing red blood cells, less attention is given to the clearance of the therapeutic nanoparticles. They wanted to distract the immune system in the most gentle way, ideally via the body's innate mechanisms rather than by artificial substances.The team found an elegant solution, which involved injecting mice with red blood cell-specific antibodies. These molecules form the basis of the mammalian immune system. They recognize the entities that need to be removed from the body, in this case RBCs. The hypothesis proved right, and a small dose of antibodies—1.25 milligrams per kilogram of body weight—turned out to be very effective, extending the blood circulation of nanoparticles dozens of times. The tradeoff was very moderate, with the mice exhibiting a mere 5% drop in RBC levels, which is half of that which qualifies as anemia.
The researchers found that their approach, called the cytoblockade of the mononuclear phagocyte system, was universally applicable to all nanoparticles. It prolonged the circulation times for tiny quantum dots measuring just 8 nanometers, medium-scale 100-nanometer particles, and large micron-sized ones, as well as the most advanced nanoagents approved for use on humans, polymer-coated "stealth" liposomes disguised under a highly inert polyethylene glycol coating to hide from the immune system. At the same time, the cytoblockade does not impair the body's ability to fend off bacteria (natural microparticles) in the bloodstream, both in small doses and in the case of sepsis.
There is a wide range of nanoparticle applications made possible by the new technology. In one series of experiments on mice, the researchers achieved a dramatic improvement in the so-called active delivery of nanoagents to cells.
It involves nanoparticles equipped with a special molecule to recognize target cells.
The experiment highlights the enormous potential of the new technology, not only for enhancing the performance of nanosized agents, but for enabling those previously completely inefficient in vivo.
The team went on to demonstrate the applicability of their technology to cancer therapy, with the cytoblockade enabling up to 23 times more efficient magnetically guided delivery of nanoparticles to the tumor.
Art work by Dr. Krishna Kumari Challa
Source: Maxim P. Nikitin et al. Enhancement of the blood-circulation time and performance of nanomedicines via the forced clearance of erythrocytes, Nature Biomedical Engineering (2020). DOI: 10.1038/s41551-020-0581-2