In a previous study, a formulation of methotrexate (MTX) incorporated in the lipid bilayer of 100-nm liposomes in the form of diglyceride ester (MTX-DG, lipophilic prodrug) was developed. In this study, first, the interactions of MTX-DG liposomes with various human and mouse tumor cell lines were studied using fluorescence techniques. The liposomes composed of egg phosphatidylcholine (PC)/yeast phosphatidylinositol/MTX-DG, 8:1:1 by mol, were labeled with fluorescent analogs of PC and MTX-DG. Carcinoma cells accumulated 5 times more MTX-DG liposomes than the empty liposomes. Studies on inhibitors of liposome uptake and processing by cells demonstrated that the formulation used multiple mechanisms to deliver the prodrug inside the cell. According to the data from the present study, undamaged liposomes fuse with the cell membrane only 1.5–2 hours after binding to the cell surface, and then, the components of liposomal bilayer enter the cell separately. The study on the time course of plasma concentration in mice showed that the area under the curve of MTX generated upon intravenous injection of MTX-DG liposomes exceeded that of intact MTX 2.5-fold. These data suggested the advantage of using liposomal formulation to treat systemic manifestation of hematological malignancies. Indeed, the administration of MTX-DG liposomes to recipient mice bearing T-cell leukemic lymphoma using a dose-sparing regimen resulted in lower toxicity and retarded lymphoma growth rate as compared with MTX.

The increasing incidence of melanoma makes this cancer an important public health problem. Therapeutic resistance is still a major obstacle to the therapy of patients with metastatic melanomas. The aim of this study was to develop the melanoma cell line resistant to DNA-alkylating agents and to elucidate the mechanisms involved in acquired drug resistance. We established a unique melanoma subline Mel MeR resistant to DNA-alkylating drug aranoza by continuous stepwise selection of the Mel Me/WT cell line with increasing concentrations of this drug. Mel MeR cells were also cross-resistant to streptozotocin or cisplatin. Here, we show that aranoza-resistant melanoma cells modulate the ABC transporter activity, upregulate the expression of PRAME, adopt a vascular-related phenotype and engage in vasculogenic mimicry. LCS1269, a vasculogenic mimicry low-molecular-weight inhibitor, reverses the sensitivity of resistant melanoma cells to DNA-damaging agents. In this study, we provide experimental evidence that LCS1269 might be considered as a new potential anticancer agent capable of overcoming multidrug resistance for DNA-damaging agents in melanoma.

Liposomes are one of the most well-known and promising nanoscale drug delivery systems. Liposomal medicinal products are successfully used in clinical practice for cardiovascular, oncological, dermatological, and other indications. The development of liposomes and their widespread implementation in clinical practice are relevant tasks.The aim of the study was to summarise and analyse scientific data regarding the structure, composition, and classification of liposomes, as well as specific aspects of liposome production methods.This review covers up-to-date information on marketed liposomal medicinal products. The authors illustrate how production methods affect the composition and structure of liposomes. The size and lamellarity are important characteristics of liposomes that determine the encapsulation efficiency and biodistribution of active pharmaceutical ingredients (APIs). The choice of excipients depends on the intended use of liposomal medicinal products. The article summarises the main liposome production methods, highlighting specific usage aspects, advantages and disadvantages. Conventional liposome production methods are easy to apply and do not require complex equipment, and their principal disadvantages include the low efficiency of API encapsulation within liposomes and the high complexity of scaling up technological processes. The authors pay special attention to microfluidic techniques for liposome preparation, which are characterised by a highly controlled technological process (in terms of size distribution and lamellarity), high reproducibility, and scalability to the level of industrial production and are applicable to encapsulating different APIs.

Liposomal targeted drug delivery makes it possible to achieve effective concentration in the target cell under various pathological conditions. The main advantage of liposomal particles is their biodegradability and immunological neutrality, which improves the safety profile of drugs. The review provides information on the composition of liposomes: the main component of the liposomal membrane is phospholipids, which provide its strength and protect from mechanical impacts. Liposomal particles are distinguished by the size and number of bilayer membranes, also secreted liposomes with a non‑lamellar organization. The composition and size of liposomes are selected depending on the purpose, including excipients in the membrane that affect the properties and functions of liposomes, including the rate of release of the components, the affinity of liposomes for the target tissue, etc. The review considers the main methods for obtaining liposomes and the features of their use, advantages and disadvantages. The creation of liposomes that are sensitive to various external or internal physicochemical factors makes it possible to realize drugs effects, localize the site of its action and reduce the number and severity of side effects. Currently, liposome‑based drugs are successfully used in various fields of medicine – dermatology, cardiology, oncology, neurology, etc. The most active condact preclinical and clinical studies of liposomal drugs for the treatment of malignant neoplasms. Particular attention is paid to the work of Russian researchers in the field of targeted drug delivery. It is shown that today liposomes are an open for study and improvement system for targeted drug delivery.

Introduction. Currently, more than 600 thousand people a year are affected by malignant tumors on the territory of the Russian Federation. Despite the large selection of antitumor drugs and the variety of mechanisms of their action, the effectiveness of existing drugs continues to be insufficient. The main disadvantages of most antitumor drugs are the emergence of tolerance to them of tumor cells, a limited range of action and high toxicity. In this regard, the creation of effective original domestic antitumor drugs still remains relevant. Among the numerous natural and synthetic heterocyclic compounds that exhibit antitumor activity, indolo[2,3-a]carbazole derivatives that can initiate various pathways of tumor cell death are of increasing interest. The main targets for their action are topoisomerases and protein kinases, which play an important role in the processes of replication, transcription, repair or recombination of deoxyribonucleic acid (DNA). Due to this, in addition to antitumor activity, this group of compounds shows antibacterial, аntiprotozoal and immunomodulatory activity, which makes them a very promising class of candidates for the creation of new drugs.Text. The purpose of this review is to discuss instrumental methods for qualitative and quantitative analysis of indolo[2,3-a]carbazole derivatives used in the world's leading pharmacopoeias. These methods can be used both in pharmacokinetic studies, and in the standardization of these compounds, in the form of pharmaceutical substances, or as part of drug forms.Conclusion. To further introduce a new group of antitumor drugs based on indole[2,3-a]carbazole derivatives into medical practice, a deep and thorough study of their physical and chemical properties is necessary. Justification and development of analysis methods allow us to develop methods applicable to pharmacokinetic studies, as well as to create regulatory documents for quality control and standardization of indolo[2,3-a] carbazole derivatives as pharmaceutical substances. A study of the literature that describes methods for analyzing indolo[2,3-a]carbazole derivatives indicates that spectrometric (infrared and ultraviolet spectrometry) and chromatographic (thin-layer chromatography and high-performance liquid chromatography) methods are most often used to determine the authenticity and quantitative analysis of these compounds.