Liposomal formulations of antitumor DRUGS. I. cholesterol effect on membrane interactions of europium coordination complexes

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: i) to characterize the membrane partition properties of these complexes, and ii) 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

Liposomal formulations of antitumor drugs. II. effect of lipid compositions on membrane interactions of europium coordination complexes

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

Partitioning of europium chelate into lipid bilayer as revealed by p-terphenyl and pyrene quenching

Fluorescence quenching method is an effective tool for obtaining important information about different properties of biophysical and biochemical systems. In the present study quenching of fluorescent probes p-terphenyl and pyrene by europium chelate were observed in phosphatidylcholine liposomes. Europium chelates (EC) belong to a new class of potential antitumor drugs with high cytotoxic activity. These compounds are of particular interest for biomedical investigations and diagnostics, since their spectral characteristics are optimal for decrease of light scattering in biological patterns and background signal. However, the application of such drugs in a free form is limited by their high toxicity and metabolic instability. One efficient way to increase drug efficiency is based on using different drug delivery systems such as liposomes. Highly adaptable liposome-based nanocarriers currently attract increasing attention, because of their advantages, viz. complete biodegradability, ability to carry both hydrophilic and lipophilic payloads and protect them from chemical degradation and transformation, increased therapeutic index of drug, flexibility in coupling with targeting and imaging ligands, improved pharmacodynamic profiles compared to the free drugs, etc. The present study was focused on examination of lipid bilayer interactions of europium chelate (here referred to as V10). Fluorescence intensity of membrane- incorporated probes – pyrene and p-terphenyl – was found to decrease with increasing concentration of the drug, suggesting that V10 represents an effective quencher for these probes. This finding was explained by the drug penetration into hydrophobic membrane core, followed by the collision between V10 and probe molecules and subsequent fluorescence quenching. The acquired fluorescence quenching data were quantitatively interpreted in terms of the dynamic quenching model

Liposomal formulations of antitumor DRUGS. I. cholesterol effect on membrane interactions of europium coordination complexes

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: i) to characterize the membrane partition properties of these complexes, and ii) 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

Partitioning of europium chelate into lipid bilayer as revealed by p-terphenyl and pyrene quenching

Fluorescence quenching method is an effective tool for obtaining important information about different properties of biophysical and biochemical systems. In the present study quenching of fluorescent probes p-terphenyl and pyrene by europium chelate were observed in phosphatidylcholine liposomes. Europium chelates (EC) belong to a new class of potential antitumor drugs with high cytotoxic activity. These compounds are of particular interest for biomedical investigations and diagnostics, since their spectral characteristics are optimal for decrease of light scattering in biological patterns and background signal. However, the application of such drugs in a free form is limited by their high toxicity and metabolic instability. One efficient way to increase drug efficiency is based on using different drug delivery systems such as liposomes. Highly adaptable liposome-based nanocarriers currently attract increasing attention, because of their advantages, viz. complete biodegradability, ability to carry both hydrophilic and lipophilic payloads and protect them from chemical degradation and transformation, increased therapeutic index of drug, flexibility in coupling with targeting and imaging ligands, improved pharmacodynamic profiles compared to the free drugs, etc. The present study was focused on examination of lipid bilayer interactions of europium chelate (here referred to as V10). Fluorescence intensity of membrane- incorporated probes – pyrene and p-terphenyl – was found to decrease with increasing concentration of the drug, suggesting that V10 represents an effective quencher for these probes. This finding was explained by the drug penetration into hydrophobic membrane core, followed by the collision between V10 and probe molecules and subsequent fluorescence quenching. The acquired fluorescence quenching data were quantitatively interpreted in terms of the dynamic quenching model