Transport for the agent
Medicines are delivered to our diseased organs by adenoviruses, nanoparticles, and also "squeezed cells"
Anton Brindley, Marina Solodovnikova, portal Милосердие.ги
Scientists create drugs for a variety of diseases. However, finding a therapeutic agent is not enough, you still need to think about and test the method of its delivery to the desired organ or tissue. We know much less about this, and yet the creators of such vehicles have made it possible, for example, to develop vaccines against the SARS-CoV-2 virus fairly quickly.
Viruses and lipid particles
The vector vaccines Sputnik V and Astra Zeneca used adenoviruses as such a vehicle. The adenovirus is able to enter the cell and drag the genetic material of the coronavirus S-protein behind it.
Russian and British scientists used a method that was created long before the pandemic and was used for gene therapy of cancer and a number of other diseases associated with genetic disorders.
Molecular biologists of the USA and Germany went the other way. They used lipid nanoparticles as a vehicle for the mRNA of the spike protein of the coronavirus. Their creator, the American company Alnylam Pharmaceuticals, for the first time used such a delivery method in its drug onpattro, intended for the treatment of a rare hereditary disease – transtiretin amyloidosis in adults. Lipid nanoparticles were used to deliver interfering RNA into the cell, which allows splitting the patient's own RNA with a disastrous mutation.
As always in medicine – a fly in the ointment
In August 2022, it became known that two young children in Russia and Kazakhstan died from acute liver failure, which developed in them within five to six weeks after administration of the drug zolgensma from spinal muscular atrophy, a rare and incurable orphan disease until recently. This is a genetically engineered drug in which an adeno-associated virus is used as a means of delivery to the cell.
Novartis draws attention to the fact that in one of the cases the child was older in age than in the indications for the use of zolgensma, and the accompanying documents indicate that the older the child, the higher the likelihood of complications when using it.
Experts note that cases of severe complications with the introduction of adenoassociated gene therapy drugs have already occurred, and in other cases – including four deaths – the liver of patients also suffered.
So far, the American state agency FDA has decided not to revoke the certificate of approval of such drugs due to the fact that they are used for extremely rare terminal diseases, for which there is no other treatment. To date, more than 2,300 children in 43 countries, including Russia, have received doses of zolgensma.
Novartis is currently working on improving the technology of introducing zolgensma intrathecally, that is, not into the blood stream, along with which the drug enters various organs, but directly into the cerebrospinal fluid. The developers of the drug hope to avoid the negative effect of the drug on the liver in this way.
There are also problems with lipid nanoparticles. Despite the fact that this method of delivery allows you to reduce the dose of the drug and, accordingly, its potential toxicity to the body, the lipid nanoparticles themselves in some cases can cause negative side effects, so scientists continue to work on improving this technology.
Another problem is the insufficient stability of drugs in which the therapeutic agent is delivered to a living cell using lipid nanoparticles.
Moderna and Pfizer vaccines require special transportation conditions. They must always be at a temperature of -70 ° C, which greatly complicates and increases the cost of logistics.
Currently, the creators of vaccines are working to increase their stability. They have already managed to increase it at 4°C from five days to one month.
Medicine for a capricious organ
A group of researchers at the Harvard Medical School Hospital, led by Wei Tao, is working to create a vehicle for the treatment of bladder cancer. The difficulty with this particular organ is that almost any therapeutic agent is washed out of it by urine.
Tao and his colleagues set about creating a nanoparticle that would attach itself firmly enough to the bladder mucosa and give the drug a chance to do its job. The active substance is aimed at activating lysine-specific demethylase (KDM6A), which suppresses tumor growth in the bladder.
Scientists used an existing lipid nanoparticle, but covered it with a special layer of polyethylene glycol, which was created using molecular engineering specifically for the purpose of binding to the mucous membrane.
In an experiment on a mouse model, this delivery method demonstrated its effectiveness: nanoparticles were attached to the mucosa, and their "filling" slowed down the growth of the tumor.
The same mice that received the drug without a protective outer layer quickly dumped it with urine and showed no improvement.
As scientists say, it is too early to celebrate success, since it is necessary to design an experiment in humans and conduct clinical trials, but already now we can talk about what in the language of scientists is called proof of concept correctness.
Intravenously and orally
Intravenous administration of the drug is considered the most effective, except in cases when the drug should not enter the bloodstream (for example, vaccines). Tablets are much more convenient for the patient, however, they slowly penetrate into the blood and, accordingly, the therapeutic effect slows down. At the same time, the bioavailability of the drug decreases, because a significant proportion of it does not have time to achieve its goal, since even before that it is excreted by the liver.
Harvard University professor Samir Mitragotri and his colleagues are working to use erythrocytes, that is, red blood cells, as a means of delivering the drug. Experimenters mix lipid nanoparticles already connected to the drug with erythrocytes, which makes it easier for them to penetrate into the tissues of the body.
Scientists suggest using such a delivery method for small molecules, biosimilars and mRNA.
At the same time, it is not always important for us that the drug quickly gets from the gastrointestinal tract into the bloodstream. If we treat the stomach or intestines, we have the opposite goal – to slow down its absorption into the blood, since the action of the drug is required in one of these organs.
To achieve this, Mitragotri's group is experimenting with the bacterium Spirulina platensis as a vehicle for curcumin, a well-known dietary supplement. They dissolved curcumin in ethanol, diluted with water and added a suspension of S. Platensis, after which the resulting mixture was shaken for 12 hours.
It is known that Spirulina platensis is delayed by thin villi of the inner intestinal mucosa and attaches to it, while the effect of the drug is prolonged and reaches its goal. Experimenters have already tried to deliver curcumin in this way to the intestines of mice suffering from acute colitis, where it reduced inflammation.
New biotechnological platform "Cell Compression"
It's a funny name, but that's how Cell Squeeze translates. Under this name, the author of the platform, Dr. Armon Sharey, executive director of the biotech company SQZ Biotechnologies, patented it.
Almost by chance, Sharey managed to discover that the cell membranes open when it passes through a narrow corridor under the influence of compression. This is a good chance to introduce the necessary therapeutic agent into the cell through a hole in the membrane.
The great advantage of this method is that the patient's own cells are used as a vehicle, which makes therapy much safer than using other transporters.
"We take peripheral blood mononuclear cells from a patient and use the method we developed to load malignant tumor antigens into them. We started working with tumors positive for human papillomavirus (HPV)," says Armon Sharey.
Cells "stuffed" with antigens are injected into the patient and activate T-killers of the immune system, which, in turn, attack the tumor.
The company has already received FDA approval to conduct clinical trials of cell therapy aimed at treating patients with tumors caused by HPV.
Sources:
Why drug delivery is the key to new medicinesSQZ Biotech’s Unique Technology Squeezes Cells to Transform Them into Therapeutics
Novartis reports two liver-related deaths with Zolgensma
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