[Study of the efficiency of cellular accumulation of doxorubicin supplied with a targeted delivery system based on phospholipid nanoparticles with integrin-directed peptide]. / Issledovanie éffektivnosti kletochnogo nakopleniia doksorubitsina, snabzhennogo targetnoi sistemoi dostavki na osnove fosfolipidnykh nanochastits c integrin-napravlennym peptidom.

Chemotherapeutic agents containing targeted systems are a promising pathway to increase the effectiveness of glioblastoma treatment. Specific proteins characterized by increased expression on the surface of tumor cells are considered as possible targets. Integrin αvß3 is one of such proteins on the cell surface. It effectively binds the cyclic Arg-Gly-Asp (cRGD) peptide. In this study, the cRGD peptide-modified doxorubicin (Dox) phospholipid composition was investigated. The particle size of this composition was 43.76±2.09 nm, the ζ-potential was 4.33±0.54 mV. Dox was almost completely incorporated into the nanoparticles (99.7±0.58%). The drug release increased in an acidic medium (at pH 5.0 of about 35±3.2%). The total accumulation and internalization of Dox used the composition of phospholipid nanoparticles with the targeted vector was 1.4-fold higher as compared to the free form. In the HeLa cell line (not expressing αvß3 integrin) this effect was not observed. These results suggest the prospects of using the cyclic RGD peptide in the delivery of Dox to glioblastoma cells and the feasibility of further investigation of the mechanism of action of the entire composition as a whole.

Nanoliposomes as drug delivery systems: safety concerns.

The review highlights the safety issues of drug delivery systems based on liposomes. Due to their small sizes (about 80-120 nm, sometimes even smaller), phospholipid nanoparticles interact intensively with living systems during parenteral administration. This interaction significantly affects both their transport role and safety; therefore, special attention is paid to these issues. The review summarises the data on the basic factors affecting the safety of nanoliposomes: composition, size, surface charge, stability, the release of an incorporated drug, penetration into tissues, interaction with the complement system. Attention is paid to the authors' own research of unique phospholipid nanoparticles with a diameter of 20-30 nm. The influence of technological processes of nanoliposome production on their properties is considered. The article also discusses the modern safety assessment criteria contained in the preliminary regulatory documents of the manufacturing countries for new nanoliposome-based drugs being developed or used in the clinic.

[Plasma high density lipoproteins phospholipds as an indirect indicator of their cholesterol efflux capacity - new suspected atherosclerosis risk factor]. / Uroven' fosfolipidov lipoproteinov vysokoi plotnosti plazmy kak kosvennyi pokazatel' ikh kholesterin-aktseptiruiushchei sposobnosti.

High density lipoproteins (HDL) are a unique natural structure, protecting the body from the development of atherosclerotic vascular lesions and cardiovascular diseases due to this ability to remove cholesterol from cells. Plasma HDL level estimated by their cholesterol content, is a common lipid parameter, and its decrease is considered as an established atherosclerosis risk factor. However, a number of studies have shown the absence of positive clinical effects after drug-induced increase in HDL cholesterol. There is increasing evidence that not only HDL concentration, but also HDL properties, considered in this review are important. Many studies showed the decrease of HDL cholesterol efflux capacity in patients with coronary heart diseases and its association with disease severity. Some authors consider a decrease of this HDL capacity as a new additional risk factor of atherosclerosis. The review summarizes existing information on various protein and lipid components of HDL with a primary emphasis on the HDL. Special attention is paid to correlation between the HDL cholesterol efflux capacity and HDL phospholipids and the ratio "phospholipids/free cholesterol". The accumulated information indicates importance of evaluation in the HDL fraction not only in terms of their cholesterol, but also phospholipids. In addition to the traditionally used lipid criteria, this would provide more comprehensive information about the activity of the reverse cholesterol transport process in the body and could contribute to the targeted correction of the detected disorders.

[The effect of lipid derivative of anti-tumor drug sarcolysin embedded in phospholipid nanoparticles in the experiments in vivo]. / Deistvie lipidnogo proizvodnogo protivoopukholevogo lekarstva sarkolizina, vkliuchennogo v fosfolipidnye nanochastitsy, na opukholi v éksperimentakh in vivo.

To improve the therapeutic properties of the antitumor agent Sarcolysin, we have previously developed and characterized a dosage form representing its ester conjugate with decanol embedded in ultra-small phospholipid nanoparticles less than 30 nm in size ("Sarcolysin-NP"). The effect of the resulting composition was investigated in vivo in comparison with the free substance of sarcolysin. The composition intravenous administration to mice showed an improvement in the pharmacokinetic parameters of sarcolysin associated with its initial higher (by 22%) level in the blood and prolonged circulation, which was also observed in mice with P388 tumor. In mice with three types of tumors - lymphocytic leukemia P388, lymphocytic leukemia L1210, and adenocarcinoma of the mammary gland Ca755 - administration of two doses of sarcolysin over a period of 7 days showed its predominant antitumor effect. The maximum tumor growth inhibition was noted for lymphocytic leukemia L1210 and adenocarcinoma of the mouse mammary gland Ca755 (at a dose of Sarcolysin-NP - 8,4 mg/kg), which was higher in comparison with free substance by more than 24% and 17%, respectively. Differences in the life span of the treated animals were revealed significantly at a dose of 10 mg/kg and amounted to 25% and 17,4% for lymphocytic leukemia P388 and L1210, respectively, and 11% for adenocarcinoma Ca755. In an experiment on rats, acute toxicity of Sarcolysin-NP administered intravenously showed that an average LD50 value 2-3 times exceeded a similar parameter for commercial preparations of free sarcolysin (Melphalan and Alkeran), which indicates its lower toxicity.

[Influence of resveratrol and dihydroquercetin inclusion into phospholipid nanopatricles on their bioavailability and specific activity].

The effects of natural polyphenols, resveratrol (RES) and dihydroquercetin (DHQ), included in phospholipid nanoparticles, have been compared with free substances of RES and DHQ in in vitro and in vivo experiments. Preincubation of healthy donor plasma low density lipoproteins (LDL) with RES or DHQ included in phospholipid nanoparticles caused a more pronounced decrease in Cu2+ induced lipid oxidation compared with the free substances, and reduced the formation of lipid peroxides products. Bioavailabilities of RES and DHQ in phospholipid formulations after oral administration in rats were increased by 1.5-2 times. In an acute hypoxia model in mice prophylactic two-week administration of RES or DHQ phospholipid formulations resulted in 25% increase in survival and 1.5-fold increase in catalase activity in brain homogenates compared to free substances. Using the model of endothelial dysfunction in rats induced by L-NAME it was shown, that RES markedly attenuated the inhibition effect of L-NAME on NO synthesis. RES in phospholipid nanoparticles had the same action at a dose 10 times lower compared to free RES. Load test with resistance (clamping of the ascending aorta for 30 sec) showed that phospholipid formulation of RES possessed more pronounced protective effect due to the stimulation of endothelial NO-synthase.