Nicotine drop: "radioactive" tobacco will help replace injections with creams and ointments

Russian scientists are creating a method for accurately determining the amount of a substance that penetrates the body and has been applied to the skin. To do this, the researchers have grown the first crop of "radioactive" tobacco, from which carbon-14 compounds will be obtained. Its atoms are clearly distinguishable in experiments using accelerator mass spectrometry, with which researchers want to study the effectiveness of a transdermal drug delivery method. In the future, this will help create external remedies that will replace injections that are painful and uncomfortable for the patient in some cases, experts told Izvestia.

Harvest of radiocarbon labeled tobacco

Scientists at Novosibirsk State University (NSU) are investigating the effectiveness of drug delivery to the body through the skin using radiocarbon-labeled (C-14) tobacco. The developed method of investigating noninvasive drug delivery using accelerator mass spectrometry ("extraction" of individual atoms from the test sample with their individual counting) will allow you to find out how much of the substance applied to the skin penetrates the body and calculate the dosage of the drugs administered. This was reported to Izvestia by the Ministry of Education and Science of the Russian Federation.

This method of administration of medicines or cosmetics involves their penetration into the body to certain depths of the skin, into the circulatory system or into internal organs. It has some advantages — some drugs lose their properties when administered orally. For this reason, they are administered by injection. For example, insulin, which often has to be administered regularly. However, this method carries some risks and discomfort for the patient. An alternative to it could be a transdermal method of drug administration, that is, the process of controlled drug delivery into the systemic bloodstream through intact skin.

First of all, it is necessary to carry out a quantitative assessment of the effectiveness of the permeability of drugs into the body, the scientists said. However, there are currently no methods for such an assessment. To solve this problem, NSU proposed using the accelerator mass spectrometry method, which uses an ion accelerator to accurately count the atoms of radiocarbon-labeled compounds.

Scientists have identified substances that have absolute permeability through the skin layers, such as nicotine, caffeine and others. They should become an internal standard for quantitative measurements of the permeability of medicinal substances into the body through the skin. Scientists are also developing niosomes, which are means of delivering substances to the body. They will contain reference substances labeled with C-14 for research using accelerator mass spectrometry and confirmation of the effectiveness of delivery vehicles.

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It can also be used in various surgical operations.

The first crop of "radioactive" tobacco has already been obtained, an in vitro study of the penetration of nicotine obtained from it through the skin of snakes and laboratory mice has been conducted. Next, a similar procedure will be performed with pig skin. At the next stage, in vivo studies with harmless nicotine derivatives will be conducted on laboratory animals.

— Tobacco plants reach adulthood at the age of three months from the moment of planting. We grew them with the assistance of the staff of the Institute of Soil Science and Agrochemistry of the Siberian Branch of the Russian Academy of Sciences, where there are special growboxes and all the necessary conditions for growing this crop have been created. A month after sowing and before harvesting, we watered the plants with a radiocarbon label," said Ekaterina Parkhomchuk, director of the NGU—NSC Accelerator Mass Spectrometry.

The scientists worked with two varieties of tobacco — "Havana" and "Samsun". It turned out that in "Samsun" radiocarbon accumulated more in the roots, and in "Havana" — in the leaves. Then it was determined which organs of the plant contain the most nicotine. It turned out to be in the leaves. Depending on the variety and method of cultivation, they accumulate from 0.2–0.3% to 1-1.5% nicotine per dry biomass. As a result of the experiment, the scientists received half a gram of nicotine labeled with C-14. It will become one of the standard substances with one hundred percent permeability through the skin for the development of drug delivery systems.

Drug delivery through the skin

In parallel, for the same purposes, scientists synthetically obtained caffeine with a high content of C-14. It is also known for its one hundred percent permeability through the skin. Currently, scientists are developing a number of substances that will then be used as internal standards.

There are many methods of drug delivery into the body, both invasive and non—invasive. Transdermal is one of the latter and is of great research interest, said Anton Astanin, Executive director of STM-Cosmetics, the company with which the study is being conducted.

— Often, far from the entire dose of the drug enters the body, most of it remains outside, cut off by the stratum corneum of the epidermis. To date, it has not been possible to determine how much of a substance has passed this barrier and reached its target, unlike oral or injectable methods of drug administration into the body," he said.

For the first time in Russia, the method of accelerator mass spectrometry with radiocarbon-labeled nicotine will be used to answer this and other questions.

The skin is a powerful barrier organ, and not all compounds are able to effectively penetrate it. Therefore, the task of quantifying what proportion of the applied substance actually reaches the systemic bloodstream or target tissues remains one of the key tasks. The use of accelerator mass spectrometry using isotopically labeled compounds, in particular carbon-14, is well known in biomedical and pharmacokinetic research and makes it possible to achieve exceptionally high measurement sensitivity when working with microdoses of substances, commented Albert Rizvanov, head of the Personalized Medicine Center of Excellence at Kazan (Volga Region) Federal University.

— The work carried out at NSU is of interest precisely from a methodological point of view — as an attempt to adapt a highly sensitive analytical approach to the tasks of transdermal pharmacokinetics. Carbon-14 is a weakly radioactive isotope and, when used in trace amounts, has long been considered a safe research tool," the scientist noted.

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For the first time, the use of accelerator mass spectrometry with labeled compounds makes it possible not to assume, but to accurately measure how much of a substance actually passes through the skin barrier, said molecular biologist Arina Kholkina.

— The method makes it possible to compare delivery systems, optimize formulas and avoid excessive doses. And choosing nicotine as a reference is a wise move: the toxin becomes a comparative molecule with guaranteed permeability, paving the way for safer and more manageable therapy," she said.

The work is carried out by NSU on the basis of the NSU Institute of Medicine and Medical Technologies at the NSU-NSC Accelerator Mass Spectrometry Center with the support of the Priority 2030 program.