Keywords
Abstract
The work summarizes some of the results of the nearly 40 years work of the authors in the field of liposomology, which started in the 80s of the last century under the leadership of Academician of the National Academy of Medical Sciences of Ukraine Alexander Viktorovich Stefanov.
It is not an easy task to create the required concentration of active medicinal substances in the target organ without affecting organs and tissues not involved in the pathological process. Over the past few years, many attempts have been made to solve this problem, and it turned out that liposomes are the best
drug carriers.
The advantages of liposomes over other drug carriers are due to their properties:
– chemical affinity with natural cell membranes;
– versatility. Liposomes are capable of carrying a wide range of pharmacologically active substances, including an additional energy sources for the cell activity and genetic material;
– liposomes biodegrade relatively easily, releasing the delivered substances. Along the way to target, liposomes reliably hide their contents from contact with the immune system and do not cause protective and allergic reactions of the organism;
– the way liposomes interact with cells, takes place in different forms. This interaction can change the properties of cell membranes, for example: viscosity and permeability; the amount of electric charge, phospholipid environment of enzymes and ion channels and, accordingly, their activity (this is why even
the so-called empty liposomes can be a biologically active agents).
Thanks to liposomes, a new way of targeting the cell appears, which can be called «membrane engineering», i. e., it becomes possible to modify the cell membrane in a given direction.
It turned out that liposomes can be not only drug carriers, but also have independent biological activity. The ability of so-called empty phosphatidylcholine liposomes (PCLs) has been demonstrated to influence the electrical and contractile activity of vascular smooth muscles. In hypoxia, PCLs restore
the normal ion permeability of the plasma membranes of vascular smooth muscles, and in rats with spontaneous arterial hypertension they improve the endothelium-dependent dilator reactions of the vessels. In addition, it was shown that «empty» PCLs effectively restore acetylcholine-induced endothelium-dependent relaxation of isolated rings of the thoracic aorta, damaged by exposure to gamma irradiation. Liposomes also restore the sensitivity of vascular tissue to acetylcholine and nitric oxide reduced after irradiation.
In order to enhance the antihypoxic and antioxidant action of liposomes, the antioxidant quercetin was introduced into their structure. The use of the liposomal form of quercetin (LF/Q) leads to a complete restoration of coronary blood flow in the post-occlusion period in acute subtotal myocardial ischemia, significantly reduces the manifestations of oxidative stress in the reperfusion period, and prevents an increase in the content of leukotrienes C4 and E4. The synthesis of prostacyclin does not decrease. The use of the LF/Q leads to a twofold decrease in the zone of myocardial necrosis. The LF/Q almost completely prevents or largely corrects disturbances in the rhythm of heart contractions and restores the contractile activity of the myocardium. The LF/Q effectively restores the function of high conductance potassium channels in irradiated rats.
The inclusion of cytochrome c in liposomes may be promising. The liposomal form of cytochrome c leads to the correction of hemostasis disorders and prevents the development of DBC syndrome in acute massive blood loss.
Numerous pathological processes such as hypertension, atherosclerosis, and impaired blood flow in the central nervous system are caused by a lack of endogenous synthesis and release of NO. In such cases, additional administration of NO can be a very effective strategy in the treatment of diseases associated with these pathological processes.
The development of modern nitric oxide donors capable of controlled and dosed release of the active ingredient is an extremely difficult task. The creation of a lipid NO delivery system capable of providing a natural release rate and the development of its stable dosage form became the next goal of our research.
Studies of the specific action of the designed liposomal form of nitric oxide (LF/NO) indicate an extremely high dilatatory, anti-ischemic activity of the LF/NO. This is confirmed by the pronounced dosedependent relaxation of the segments of the intact rat aorta and the prolonged hypotensive reaction of the
systemic circulation. LF/NO prevents the development of critical disorders of the heart pumping function and contributes to the preservation of its contractile activity during subtotal ischemia. The action of the LF/NO is also manifested by a significant dose-dependent relaxation of the stripes of the cavernous bodies of the penis and myometrium.
The new NO-containing liposomal construct effectively opens single calcium-dependent potassium channels of high conductance in vascular smooth muscles and significantly increases the probability of their being in the open state.
Thus, the liposomal form of nitric oxide promises to be effective in the treatment of angiopathies of various origins (including diabetic), erectile dysfunction, overactive bladder, arterial hypertension, and hemorrhagic and ischemic stroke. Given the possibility of use in inhalation form, it can be used to treat
pulmonary hypertension.
The opinion is expressed that the potentialities of liposomes are significantly higher than those known to us. We have just begun to understand how liposomes work with the cell.