In previous articles, we discussed the types and properties of polynucleotides, as well as the safety of their use in cosmetology. This time we propose to evaluate how modern science has advanced in the theoretical and practical study of drugs based on these biopolymers. The article discusses available publications and reviews the prospects for the use of PDRN in various fields of medicine, including cosmetology.
Introduction
The history of science's acquaintance with nucleic acids, and, in particular, with polydeoxyribonucleotides (PDRN), began in 1868. This substance, isolated from cell nuclei, had such a complex structure that until 1962 – the moment when the structure of DNA was finally deciphered – for research, as well as for therapeutic purposes, it was used unchanged.
After the structure of PDRN was understood, they began to be divided into smaller structural parts. In addition, scientists managed to synthesize individual nucleosides, and in the 60-70s of the XX century, create a new type of medicine. These were products such as methyluracil ointment, intended for the treatment of wounds, or derinat, the sodium salt of deoxyribonucleic acid, used as an immunostimulant.
Every branch of science has its ups and downs. Starting from the late 1970s, interest in the study of PDRN was reduced and resumed in the 1990s with the development of molecular biology methods, as well as cell technologies. Previously inaccessible to a wide range of researchers, new technologies penetrated routine laboratory activities. This led to the emergence of such a direction as genetic engineering. [1]
With the development of understanding of the internal structure of the subtle world, drugs based on PDRN were improved – it became possible to synthesize exactly those segments of the polymer chain that are needed to develop or restrain various processes occurring in a living organism. Currently, the mechanisms of such interactions are being actively studied. In particular, targeted therapy is especially relevant, which allows using a synthetic short-stranded DNA molecule to trigger the degradation mechanisms of viruses and tumors, as well as to influence the production and action of various cytokines.
Methods for obtaining PDRN
It is logical to assume that active research work, as well as ensuring the production of medical devices and cosmetics, requires a significant amount of raw materials. How is PDRN obtained?
In general, there are two types of PDRN: synthetic and semi-synthetic, or biotechnological. Synthetic DNA is obtained using special synthesizers by the method of solid-phase synthesis. From an economic point of view, this method is justified for obtaining oligonucleotides (up to 20-30 nucleosides per chain). The resulting product is intended for research or the production of substances for targeted therapy.
Biotechnological PRRN can have a variety of origins – nucleic acids can be isolated from any cell, be it a plant or an animal. (FIGURE 1) The main sources of PDRN for biotechnology are fish milt, mainly salmon or cod, and calf thymus. As practice shows, substances isolated from different types of living organisms differ in chain length, but when used for therapeutic purposes for the treatment of wounds, they produce a similar effect. [2]
The process of obtaining PDRN from organic raw materials is a multi-stage process, and in a simplified form is described as the destruction of cell and nuclear walls, followed by the release of nucleic acids. Next, the resulting intermediate is purified and standardized, i.e., its chemical structure and purity are checked. In this form, PDRN is ready for use or further treatment.
PDRN in medicine
Over the past 10 years, therapeutic drugs based on the PDRN substance have been greatly improved. It is worth noting that we deliberately do not consider the successes of targeted therapy and research in the field of genetic engineering, so as not to complicate the text. All the facts below are relevant to the injection or external use of PDRN.
Let us start with reconstructive surgery. Currently widely known materials for synovial fluid prosthetics based on hyaluronan. In 2009, a patent was registered for a composition for the treatment of osteoarticular diseases based on PRRN, intended for injection into the joint [3]. In addition to conducting toxicological tests confirming the safety of the invention, the scientists found that the result of using the PDRN-based product is comparable to the results of using hyaluronan. [4]
In addition to replacing and replenishing the synovial fluid, it is also possible to build up bone tissue. Thus, Italian scientists have shown that the combined use of PDRN and material for osteoprosthetics contributes to a faster and more effective restoration of bone tissue. [5]
In modern literature, there are many references to the ability of PRRN to accelerate skin regeneration. Thus, this substance has been studied in mice in order to heal postoperative scars [6], (FIGURE 2) as well as in the treatment of diabetic foot syndrome [7]. As a result, it was shown that the improvement in the state of tissues occurs due to an increase in the saturation of the affected areas, as well as due to the stimulation of neoangiogenesis and, accordingly, the development of the circulatory system in the injured skin. (FIGURE 3) These results indicate a reduction in the likelihood of tissue necrosis, making the method promising for routine practice.
Fig. 2. Histological assessment (hematoxylin and eosin) of post-operative flap healing against the background of ischemic tissue damage performed on days 5 and 10 after surgery (ten-fold increase). A – Placebo therapy (saline), day 5: no healing process. B – Polynucleotide therapy, day 5: incomplete healing. C – Placebo therapy, day 10: poor healing process; education of granulomatous tissue. D – Polynucleotide therapy, day 10: recovery, normal skin architecture. (Source: https://www.sciencedirect.com/science/article/pii/S0741521411018386)
Fig. 3. Histological assessment (hematoxylin and eosin) of diabetic foot tissues before and after treatment with PDRN. A – Before treatment. Tissue necrosis is marked with a black ellipse. B – After the course of treatment – reductionn of inflammation. C – Vascularization before therapy, vessels are indicated by yellow arrows. D – Vascularization after therapy, vessels are indicated by yellow arrows. (Source: https://www.researchgate.net/publication/320644842_Polydeoxyribonucleotide_PDRN_Improves_Peripheral_...)
A similar effect is observed not only in living organisms, but also in experiments with cell cultures. For example, the use of human fibroblasts as an example was shown that the combined use of hyaluronan and PDRN causes enhanced cell growth [8].
Using human keratinocytes as an example, the kinetics of the inflammatory process in the presence of PDRN was studied [9]. The study showed that, compared with ribonucleinates, the reduction of inflammation is more effective under the influence of deoxyribonucleinates.
PDRN in aesthetic cosmetology
Of course, speaking about aesthetic cosmetology, it is interesting to get acquainted with the results that are closer to real tasks. For example, practitioners are familiar with the situation with the restoration and healing of the skin after CO2 laser exposure. Researchers have proposed the use of PDRN-based injections to restore and normalize the skin. The study was conducted on rats and showed interesting results. [10] Compared with the group of animals receiving injections of placebo (physiological sodium chloride solution), accelerated healing of damaged skin tissues was noted. This result speaks to the safety and applicability of PDRN-based drugs even after aggressive procedures.
Conclusion
Already, PDRN has an interesting and detailed evidence base. The data presented above demonstrates the effectiveness and safety of this ingredient. Moreover, its reparative properties, as well as the minimum load on the immune system, allow the use of products based on it even during the recovery period after aggressive procedures and even plastic surgery.
Literature
1. Khvorova A, Watts JK. The chemical evolution of oligonucleotide therapies of clinical utility. Nat Biotechnol. 2017 Mar;35(3):238-248.
2. Jong Hun Lee et al. Comparison of wound healing effects between Oncorhynchus keta-derived polydeoxyribonucleotide (PDRN) and Oncorhynchus mykiss-derived PDRN. Archives of Craniofacial Surgery. Vol. 19, No. 1, 20-34.
3. Cattarini-Mastelli L., Cattarini-Mastelli J. Injectable composition based on polydeoxyribonucleotides for the treatment of osteoarticular diseases. Patent of the RF No. 2508115.
4. Ancuța Zazgyva et al. Polynucleotides versus sodium hyaluronate in The local treatment of knee osteoarthritis. AMT, v. II, no. 2, 2013, p. 260-263
5. Barbara Buffoli et al. Sodium-DNA for Bone Tissue Regeneration: An Experimental Study in Rat Calvaria. BioMed Research International. Vol. 2017, Article ID 7320953, 9 pages
6. Francesca Polito et al. Polydeoxyribonucleotide restores blood flow in an experimental model of ischemic skin flaps. Journal of Vascular Surgery. Vol. 55, Is. 2, Febr. 2012, Pages 479-488
7. Kim S et al. The effects of PDRN on diabetic feet. Archieves of Plastic Surgery 2017;44:482-489
8. Stefano Guizzardi et al. Hyaluronate Increases Polynucleotides Effect on Human Cultured Fibroblasts. Journal of Cosmetics, Dermatological Sciences and Applications, 2013, 3, 124-128
9. Judit Danis et al. Differential Inflammatory-Response Kinetics of Human Keratinocytes upon Cytosolic RNA- and DNA-Fragment Induction. Int. J. Mol. Sci. 2018, 19(3), 774
10. Mi Yu & Jun Young Lee. Polydeoxyribonucleotide improves wound healing of fractional laser resurfacing in rat model. Journal of Cosmetics, Dermatological Sciences and Applications, 2017, Vol. 19, Is. 1, Pages 43-48
Fig. 1. DNA quality assessment by electrophoresis. From left to right: markers of DNA molecules of different lengths; high-quality DNA, homogeneous in molecular weight; low-quality DNA (Source: https://blog.genotek.ru/dna-isolation-practice)
Fig. 2. Histological assessment (hematoxylin and eosin) of post-operative flap healing against the background of ischemic tissue damage performed on days 5 and 10 after surgery (ten-fold increase). A – Placebo therapy (saline), day 5: no healing process. B – Polynucleotide therapy, day 5: incomplete healing. C – Placebo therapy, day 10: poor healing process; formation of granulomatous tissue. D – Polynucleotide therapy, day 10: recovery, normal skin architecture. (Source: https://www.sciencedirect.com/science/article/pii/S0741521411018386)
Fig. 3 Histological assessment (hematoxylin and eosin) of diabetic foot tissues before and after treatment with PRNC. A – Before processing. Tissue necrosis is marked with a black ellipse. B – After the course of treatment – reduction of inflammation. C – Vascularization before therapy, vessels are indicated by yellow arrows. D – Vascularization after therapy, vessels are indicated by yellow arrows. (Source: https://www.researchgate.net/publication/320644842_Polydeoxyribonucleotide_PDRN_Improves_Peripheral_...)
Fig. 4. Photographs of the dynamics of skin healing in mice treated with an ablative CO2-laser obtained during the application of PDRN (top) and placebo (bottom). (Source: [10])
