Development of new formulations of antineoplastic drugs currently represents extensively growing research area. Efficiency of existing anti-tumor drugs is frequently limited by their high general toxicity, metabolic instability in an organism and bad penetration into a cancer cell. Besides, insignificant direct influence on tumoral growth also limits the application of antineoplastic drugs in a free form. One efficient way of drug delivery is based on the use of lipid vesicles (liposomes). Liposomes are spherical, self-closed structures formed by one or several concentric lipid bilayers with an aqueous phase inside and between the lipid bilayers. The lipid bilayer favors solubilization of hydrophobic compounds, whereas internal aqueous phase of lipid vesicles is suitable for encapsulation of hydrophilic drugs. Design of liposomal carriers is heavily based on the evaluation of bilayer-modifying properties of the drug. This is important not only for achieving maximum payload without compromising liposome stability, but also for prediction of therapeutic and toxic effects of a certain compound, because membrane interactions may prove critical for drug absorption, distribution, metabolism and elimination in an organism. In the present work the effect of the two potential antineoplastic drugs - europium coordination complexes (LC) - on the physicochemical properties of phosphatidylcholine (PC) model membranes has been investigated using the environmentally-sensitive pH indicator dye bromothymol blue (BTB). This dye responds to the changes in environmental conditions by the shifts of its protolytic and partition equlibria. Incorporation

of LC into the lipid vesicles was found to exert no influence on the effective electrostatic potential of model membranes, i.e. the mean potential at location of the dye prototropic moiety in the interfacial region. In contrast, BTB membrane partitioning markedly enhanced in the presence of drugs, indicating that europium coordination complexes can affect molecular organization of a lipid bilayer, presumably through generation of structural defects and altering the conformation of PC headgroups. High lipophilicity of Eu(III) coordination complexes together with their relatively weak membrane-modifying propensities create prerequisites for the development of liposomal formulations of these compounds.

Among a wide variety of drug nanocarriers developed to date, liposome-based delivery systems are particularly attractive due to their advantageous features such as biocompatibility, complete biodegradability, low toxicity, ability to carry both hydrophilic and lipophilic payloads and protect them from chemical degradation and transformation, increased therapeutic index of a drug, improved pharmacokinetic and pharmacodynamic profiles compared to free drugs, reduced side effects, etc. The efficiency of drug encapsulation is largely determined by its membrane-partitioning properties as well as physicochemical characteristics of the lipid vesicles. In the present study we concentrated our efforts on the pre-formulation studies of the two synthesized Eu(III) coordination complexes, V3 and V4, the potential anticancer drugs. More specifically, our goal was twofold: to characterize the membrane partition properties of these complexes, and to assess how the lipid-associating ability of V3 and V4 depends on membrane structural state being varied by introducing the different amounts of cholesterol

(Chol) into phosphatidylcholine (PC) lipid vesicles. To achieve this goal, several fluorescent probes including pyrene, 1,6-diphenyl-1,3,5-hexatriene (DPH), and 4-p-(dimethylaminostyryl)-1-dodecylpyridinium (DSP-12) have been employed. Partition coefficients of lanthanides determined using the equilibrium dialysis technique proved to depend on the amount of Chol content. Formation of drug-lipid complexes was found to affect pyrene excimerization and DSP-12 spectral properties but exerted no influence on pyrene vibronic structure and DPH anisotropy. Membrane composition was shown to have an impact on the spectral responses of the probes in drug-lipid systems. This finding was interpreted as arising from the sterol condensing effect on the structural state of the lipid bilayer.

Currently there is a growing interest in screening of new drugs, capable of destroying cancer cells effectively, without damaging health tissues. In this context the potential of liposomes as a drug carrier system is extensively investigated [1-3]. Liposomes are nanosize particles in which lipid bilayer encloses an aqueous internal compartment. Size, charge and surface properties of liposomes can be easily changed simply by adding new ingredients to the lipid mixture before liposome preparation or by variation of preparation techniques. Another important feature is that lipid vesicles can entrap both hydrophilic and hydrophobic pharmaceutical agents. Liposome delivery systems can enhance drug solubility, reduce toxicity associated with free anticancer drugs and improve stability of the drug by protecting the compound from chemical degradation or transformation. However, the therapeutic and toxic effects of drug are strongly determined by the degree or efficiency of its loading into the liposomes. For this reason, while using liposomes as delivery systems for hydrophobic drugs, it is necessary to know the character of a drug effect on the structure and physicochemical properties of a lipid bilayer. The aim of this work was to investigate the effect of lipid composition on membrane interactions of europium coordination complexes, V3 and V4, the potential antineoplastic drugs. Liposomes were formed by egg yolk phosphatidylcholine (PC) and its mixture with cardiolipin (CL) and cetyltrimethylammonium bromide (CTAB). The membrane-partitioning properties of the investigated drugs were

evaluated using the equilibrium dialysis technique in combination with absorption spectroscopy. To gain insight into the drug influence on physical parameters and molecular organization of lipid bilayer, two fluorescent probes have been employed, viz. pyrene and 1,6-diphenyl-1,3,5-hexatriene (DPH). It was found that inclusion of anionic lipid cardiolipin and cationic detergent CTAB into PC bilayer gives rise to decrease of the drugs partition coefficients. The drug incorporation into liposomal membrane is accompanied by the alterations of pyrene spectral parameters and DPH anisotropy. The observed effects suggest that the influence of europium compounds on bilayer structural state can be modulated by CL and CTAB.

За допомогою методу моношарів Ленгмюра досліджено здатність нових протипухлинних препаратів, координаційних комплексів європію (ККЄ), вбудовуватися у ліпідний моношар, сформований з дімірістоїлфосфатидилхоліну. Знайдено, що ККЄ проникають у ліпідний моношар, а ступінь проникнення залежить як від структури препарату, так і від начального поверхневого тиску ліпідної плівки. Оцінка критичного поверхневого тиску моношару показала, що досліджувані препарати можуть вбудовуватися у клітинні мембрани.