Efficacy and safety of phospholipid nanoparticles (VBI-S) in reversing intractable hypotension in patients with septic shock: a multicentre, open-label, repeated measures, phase 2a clinical pilot trial.

Background: Since the 1990's attempts to favorably modulate nitric oxide (NO) have been unsuccessful. We hypothesized that because NO is lipophilic it would preferentially localize into intravascularly infused hydrophobic nanoparticles, thereby reducing its bioavailability and adverse effects without inhibiting its production. We aimed to determine the efficacy and safety of intravenous infusion of a fluid comprised of hydrophobic phospholipid nanoparticles (VBI-S) that reversibly absorb NO in the treatment of hypotension of patients in severe septic shock. Methods: This is a multicentre, open-label, repeated measures, phase 2a clinical pilot trial done at six hospital centers in the USA. Patients in severe septic shock were enrolled after intravenous fluid therapy had failed to raise mean arterial blood pressure (MAP) to at least the generally accepted level of 65 mmHg, requiring the use of vasopressors. The primary endpoint of this study is the proportion of patients in whom MAP increased by at least 10 mmHg. VBI-S was administered intravenously to patients as boluses of 100 ml, 200 ml, 400 ml, and 800 ml at 999 ml/min until the blood pressure goal was reached after which the infusion was stopped, and the MAP was recorded. All patients who received any volume of VBI-S were included in the primary and safety analysis. The study is registered with ClinicalTrials.gov, NCT04257136. Findings: Between February 17, 2020 and January 3, 2023, 20 eligible patients were enrolled in the study. In all 20 (100%) patients, the goal of increasing MAP by at least 10 mmHg using VBI-S was achieved (p = 0.0087, effect size = 0.654). Mean VBI-S volume required to meet the primary goal was 561.0 ± 372.3 ml. The goal of lowering vasopressor dose was also achieved (p = 0.0017). Within 48 h or less after VBI-S, there was a statistically significant improvement in oxygenation, serum creatinine, clotting variables, procalcitonin, lactic acid, and the sequential organ failure assessment (SOFA) score. At 24 h and 48 h following administration of VBI-S, 12/15 (80%) and 9/12 (75%) patients developed hyperlipidemia, respectively. No severe adverse events of VBI-S were observed, and there were no treatment-related deaths. Interpretation: These preliminary findings suggest the safety and efficacy of VBI-S in treating hypotension in patients with septic shock. However, a definitive mortality benefit cannot be demonstrated without a randomized controlled study. Funding: The Naval Medical Research Command-Naval Advanced Medical Development program via the Medical Technology Enterprise Consortium.

A dual-vector phospholipid nanosystem of doxorubicin: accumulation and cytotoxic effect in breast cancer cells in vitro.

Various chemotherapeutic agents are used to treat breast cancer (BC); one of them is the anthracycline antibiotic doxorubicin (Dox), which, in addition to its cytostatic effect, has serious side effects. In order to reduce its negative impact on healthy organs and tissues and to increase its accumulation in tumors, Dox was incorporated into phospholipid nanoparticles. The additional use of vector molecules for targeted delivery to specific targets can increase the effectiveness of Dox due to higher accumulation of the active substance in the tumor tissue. The integrin αvß3, which plays an important role in cancer angiogenesis, and the folic acid receptor, which is responsible for cell differentiation and proliferation, have been considered in this study as targets for such vector molecules. Thus, a phospholipid composition of Dox containing two vector ligands, cRGD peptide and folic acid (NPh-Dox-cRGD-Fol(3,4)), was prepared. Study of the physical properties of the developed composition NPh-Dox-cRGD-Fol(3,4) showed that the average particle size was 39.62±4.61 nm, the ζ-potential value was 4.17±0.83 mV. Almost all Dox molecules were incorporated into phospholipid nanoparticles (99.85±0.21%). The simultaneous use of two vectors in the composition led to an increase in the Dox accumulation in MDA-MB-231 BC cells by almost 20% as compared to compositions containing each vector separately (folic acid or the cRGD peptide). Moreover, the degree of Dox internalization was 22% and 24% higher than in the case of separate use of folic acid and cRGD peptide, respectively. The cytotoxic effect on MDA-MB-231 cells was higher during incubations with the compositions containing folic acid as a single vector (NPh-Dox-Fol(3,4)) and together with the RGD peptide (NPh-Dox-cRGD-Fol(3,4)). Experiments on the Wi-38 diploid fibroblast cell line have shown a significantly lower degree of cytotoxic effect of the phospholipid composition, regardless of the presence of the vector molecules in it, as compared to free Dox. The results obtained indicate the potential of using two vectors in one phospholipid composition for targeted delivery of Dox.

Effect of an NGR Peptide on the Efficacy of the Doxorubicin Phospholipid Delivery System.

This study is a continuation of an investigation into the effect of a targeted component, a peptide with an NGR, on the properties of the previously developed doxorubicin phospholipid delivery system. The NGR peptide has an affinity for aminopeptidase N (known as the CD13 marker on the membrane surface of tumor cells) and has been extensively used to target drug delivery systems. This article presents the results of a study investigating the physical properties of the phospholipid composition with and without the peptide chain: particle size, zeta potential, stability in fluids, and dependence of doxorubicin release from nanoparticles at different pH levels (5.0, 6.5, 7.4). The cytotoxic effect of the compositions has also been shown to depend on the dose of the drug used for incubation, the presence of the targeted component in the composition, and the time of incubation time of the substances. There was a significant difference in the cytotoxic effect on HT-1080 (CD13-positive) and MCF-7 (CD13-negative) cells. Cell death pathway analysis has shown that death occurred mainly by apoptosis. We also present data on the effect of doxorubicin embedded in phospholipid nanoparticles with the targeted peptide on DNA assessed by differential pulse voltammetry, the mechanism of action being electrostatic interactions. The interactions of native dsDNA with doxorubicin encapsulated in phospholipid nanoparticles with the targeted peptide were studied electrochemically by differential pulse voltammetry. Here, we have highlighted that the targeted peptide in the doxorubicin composition moved specific interaction of the drug with dsDNA from intercalative mode to electrostatic interactions.

[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.

Drug Transport System Based on Phospholipid Nanoparticles: Production Technology and Characteristics.

One of the current trends in modern pharmaceuticals is the supply of drugs by transport systems. The use of delivery systems allows to increase the therapeutic efficacy, tolerability, and safety of drug therapy. Liposomes, polymer nanoparticles, carbon nanoparticles, blood cells, metal nanoparticles, oxides, etc., are used as transport systems. This work is aimed at obtaining a finished technological product based on soy phospholipids with particle size in the nanometer range and reproducible characteristics (size, charge). For this purpose, we carried out investigations to select the optimal conditions of technological process. The developed technology makes it possible to obtain phospholipid nanoparticles without the use of any solubilizers and/or surfactants, which increases its practical relevance for further work. The versatility of the technology is demonstrated by the example of incorporation of drugs of various chemical nature and pharmacotherapeutic groups.

Chlorin e6 Phospholipid Delivery System Featuring APN/CD13 Targeting Peptides: Cell Death Pathways, Cell Localization, In Vivo Biodistribution.

We have previously designed a phospholipid delivery system for chlorin e6 to increase the efficacy of photodynamic therapy involving a second-generation photosensitizer. Further research into the matter led to double modification of the obtained nanoparticles with ligands exhibiting targeting and cell-penetrating effects: an NGR-containing peptide and heptaarginine (R7), respectively. This study investigated the cell death pathway on HT-1080 tumor cells after treatment with the proposed compositions: the chlorin e6 phospholipid composition and the two-peptide chlorin e6 phospholipid composition. It was demonstrated that most of the cells died by apoptosis. Colocalization analysis of chlorin e6 in the phospholipid composition with two peptides showed mitochondria are one of the targets of the photosensitizer. An HT-1080 tumor-bearing mouse model was used to evaluate the biodistribution of the drug in tumor, liver, and kidney tissues after administration of the study compositions in comparison with free chlorin e6. The photosensitizer mostly accumulated in the tumor tissue of mice administered the phospholipid compositions, and accumulation was increased 2-fold with the peptide-containing composition and approximately 1.5-fold with the unenhanced composition, as compared with free chlorin e6. The enhancement of the chlorin e6 phospholipid composition with targeting and cell-penetrating peptides was found to be effective both in vitro and in vivo.

In Situ Visualization of Dynamic Cellular Effects of Phospholipid Nanoparticles via High-Speed Scanning Ion Conductance Microscopy.

Phospholipid nanoparticles have been actively employed for numerous biomedical applications. A key factor in ensuring effective and safe applications of these nanomaterials is the regulation of their interactions with target cells, which is significantly dependent on an in-depth understanding of the nanoparticle-cell interactions. To date, most studies investigating these nano-bio interactions have been performed under static conditions and may lack crucial real-time information. It is, however, noteworthy that the nanoparticle-cell interactions are highly dynamic. Consequently, to gain a deeper insight into the cellular effects of phospholipid nanoparticles, real-time observation of cellular dynamics after nanoparticle introduction is necessary. Herein, a proof-of-concept in situ visualization of the dynamic cellular effects of sub-100 nm phospholipid nanoparticles using high-speed scanning ion conductance microscopy (HS-SICM) is reported. It is revealed that upon introduction into the cellular environment, within a short timescale of hundreds of seconds, phospholipid nanoparticles can selectively modulate the edge motility and surface roughness of healthy fibroblast and cancerous epithelial cells. Furthermore, the dynamic deformation profiles of these cells can be selectively altered in the presence of phospholipid nanoparticles. This work is anticipated to further shed light on the real-time nanoparticle-cell interactions for improved formulation of phospholipid nanoparticles for numerous bioapplications.

Study of Physico-Chemical Properties and Morphology of Phospholipid Composition of Indomethacin.

Nonsteroidal anti-inflammatory drugs (NSAIDs), inhibitors of cyclooxygenase-2, an enzyme involved in the formation of anti-inflammatory prostaglandin PGE2, are the most common treatment for chronic inflammatory diseases, such as, for example, arthritis. One of the most commonly used drugs of this class is indomethacin, a derivative of indolylacetic acid. In this work, we studied the physicochemical properties of the phospholipid composition of indomethacin obtained earlier (codenamed "Indolip") and the effect of freeze drying on its parameters. It was shown that the properties such as particle size, light transmission, phospholipid oxidation index did not change significantly, which indicated the stability of the drug after lyophilization. Measurement of the spectra of small-angle neutron scattering has shown that morphologically, Indolip is a vesicle whose radius is five times greater than the value of the bilayer thickness.

Chemopreventive efficacy of salvianolic acid B phospholipid complex loaded nanoparticles against experimental oral carcinogenesis: implication of sustained drug release.

Background: Although we have previously demonstrated that phospholipid complex loaded nanoparticles (PLC-NPs) encapsulating salvianolic acid B (SAB) can enhance anticancer activity in head and neck cancer and precancerous cells in vitro, the chemopreventive efficacy of SAB-PLC-NPs (nano-SAB) in vivo remains unclear. Here, we aimed to investigate the in vivo efficacy of nano-SAB against experimental oral carcinogenesis. Methods: Oral tongue carcinogenesis was induced in C57BL/6 mice through the administration of 4-nitroquinoline-N-oxide (4NQO, 100 µg/mL) in drinking water for 22 weeks. To preliminarily evaluate the effect of sustained drug release against oral carcinogenesis, free- or nano-SAB (16.6 mg/kg/d) was administered orally for 18 weeks, and the treatment was discontinued for the remaining 4 weeks. Results: Histological evaluation revealed a significant (P<0.05) decrease in the incidence of carcinoma in free-SAB-treated (16.7%) and nano-SAB-treated (10.0%) mice compared to mice exposed to 4NQO alone (34.3%). A decrease in carcinoma growth rate was also observed in free-SAB-treated (12.2%) and nano-SAB-treated (5.5%) mice compared to the 4NQO-exposed group (18.3%), even after drug withdrawal for 4 weeks. Immunohistochemical analysis revealed that nano-SAB treatment effectively suppressed Ki-67, proliferative cell nuclear antigen (PCNA), and cyclin D1 expression in high-risk dysplastic lesions compared to free-SAB-treated and 4NQO-exposed groups (all P<0.05). Importantly, nano-SAB maintained low levels of Ki-67, PCNA, and cyclin D1 expression even after drug withdrawal for 4 weeks. Conclusions: Together with our previous in vitro data, this in vivo study confirms that nano-SAB has superior chemopreventive efficacy by promoting more potent anti-proliferation and cell cycle arrest responses. These findings demonstrate the potential of SAB-PLC-NPs as promising chemopreventive agents for treating oral carcinogenesis.

[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.

Composite phospholipid-gold nanoparticles with targeted fragment for tumor imaging.

Gold nanoparticles and their conjugates have significant potential in the field of diagnosis of various diseases due to their SPR, which enhances light scattering and absorption. Conjugates of gold nanoparticles with various ligands can be used for imaging biomolecules or detecting malignant neoplasms at an early stage. This study focuses on the construction of composite (or hybrid) phospholipid-gold nanoparticles using soy phosphatidylcholine and a targeted ligand (folic acid derivative) to attach specific targeting properties. According to the method of dynamic light scattering, the diameter of the obtained nanoparticles was less than 100 nm, the results of the MTT test indicated their moderate cytotoxicity. In vitro and in vivo experiments showed a significant increase in the accumulation of phospholipid-gold nanoparticles with a targeted fragment compared to those without a targeted fragment both in HeLa cells and in a tumor (in BDF mice with an injected LLC tumor). The resulting nanoparticles are suitable for specific delivery into tumor cells and visualization of various malignant neoplasms, including at early stages, due to the increased expression of the folate receptor characteristic of cells of a wide range of tumors.

Electrochemical studies of the interaction of rifampicin and nanosome/rifampicin with dsDNA.

The interactions of dsDNA with rifampicin (RF) or with rifampicin after encapsulation in phospholipid micelles (nanosome/rifampicin) (NRF) were studied electrochemically. Screen-printed electrodes (SPEs) modified by stable dispersions of multi-wolled carbon nanotubes (MWCNTs) in aqueous solution of poly(1,2-butadiene)-block-poly(2-(dimethylamino)ethyl methacrylate) (PB290-b-PDMAEMA240) diblock copolymer were used for quantitative electrochemical investigation of direct electrochemical oxidation of guanine at E = 0.591 V (vs. Ag/AgCl) and adenine at E = 0.874 V (vs. Ag/AgCl) of dsDNA and its change in the presence of RF or NRF. Due to RF or NRF interaction with dsDNA, the differential pulse voltammetry (DPV) peak currents of guanine and adenine decreased and the peak potentials shifted to more positive values with increasing drug concentration (RF or NRF). Binding constants (Kb) of complexes RF-dsDNA and NRF-dsDNA were calculated based on adenine and guanine oxidation signals. The Kb values for RF-dsDNA were 1.48 × 104 M-1/8.56 × 104 M-1, while for NRF-dsDNA were 2.51 × 104 M-1/1.78 × 103 M-1 (based on adenine or guanine oxidation signals, respectively). The values of Kb revealed intercalation mode of interaction with dsDNA for RF and mixed type of interaction (intercalation and electrostatic mode) for NRF. The estimated values of ΔG (Gibbs free energy) of the complex formation confirmed that drug-dsDNA interactions are spontaneous and favourable reactions.

Chlorin e6 embedded in phospholipid nanoparticles equipped with specific peptides: Interaction with tumor cells with different aminopeptidase N expression.

A promising direction in Biopharmaceuticals is the development of specific peptide-based systems to improve drug delivery. This approach may increase tumor specificity and drug penetration into the target cell. Similar systems have been designed for several antitumor drugs. However, for photodynamic therapy drugs, such studies are not yet enough. Previously, we have developed a method of inclusion of chlorin e6 (Ce6), a photosensitizer used in photodynamic therapy, in phospholipid nanoparticles with a diameter of up to 30 nm, and reported an increase in its effectiveness in the experiments in vivo. In this work, we propose to modify a previously developed delivery system for Ce6 by the addition of cell-penetrating (R7) and/or targeting NGR peptides. The interaction of the compositions developed with HepG2 and MCF-7 tumor cells is shown. The expression of CD13 protein with affinity to NGR on the surface of these cells has been studied using flow cytometry. The expression of this protein on the HepG2 cells and its absence on MCF-7 was demonstrated. After incubation of tumor cells with the resulting Ce6 compositions, we evaluated the cellular accumulation, photoinduced, and dark cytotoxicity of the drugs. After irradiation, the highest level of cytotoxicity was observed when R7 peptide was added to the system, either alone or in combination with NGR. In addition to R7, the NGR-motif peptide increased the internalization of Ce6 in HepG2 cells without affecting its photodynamic activity. In this work we also discuss possible mechanisms of action of the cell-penetrating peptide when attached to phospholipid nanoparticles.

[Targeted drug delivery system for doxorubicin based on a specific peptide and phospholipid nanoparticles]. / Sistema adresnoi dostavki dlia doksorubitsina na osnove spetsificheskogo peptida i fosfolipidnykh nanochastits.

Doxorubicin is one of the widely known and frequently used chemotherapy drugs for the treatment of various types of cancer, the use of which is difficult due to its high cardiotoxicity. Targeted drug delivery systems are being developed to reduce side effects. One of the promising components as vector molecules (ligands) are NGR-containing peptides that are affinity for the CD13 receptor, which is expressed on the surface of many tumor cells and tumor blood vessels. Previously, a method was developed for preparing a composition of doxorubicin embedded in phospholipid nanoparticles with a targeted fragment in the form of an ultrafine emulsion. The resulting composition was characterized by a small particle size (less than 40 nm) and a high degree of incorporation of doxorubicin (about 93%) into transport nanoparticles. When assessing the penetrating ability and the degree of binding to the surface of fibrosarcoma cells (HT-1080), it was shown that when the composition with the targeted fragment was added to the cells, the level of doxorubicin was almost 2 times higher than that of the liposomal form of doxorubicin, i.e. the drug in the system with the targeted peptide penetrated the cell better. At the same time, on the control line of breast adenocarcinoma cells (MCF-7), which do not express the CD13 receptor on the surface, there was not significant difference in the level of doxorubicin in the cells. The data obtained allow us to draw preliminary conclusions about the prospects of targeted delivery of doxorubicin to tumor cells when using a peptide conjugate containing an NGR motif and the further need for its comprehensive study.

[Chlorine e6 in phospholipid nanoparticles with specific targeting and penetrating peptides as prospective composition for photodynamic therapy of malignant neoplasms]. / Khlorin e6 v fosfolipidnykh nanochastitsakh so spetsificheskimi adresnymi i pronikaiushchimi peptidami kak perspektivnaia kompozitsiia dlia fotodinamicheskoi terapii zlokachestvennykh novoobrazovanii.

Cytotoxic and photoinduced activity of chlorine e6 (Ce6) in phospholipid nanoparticles with specific tumor targeting and cell-penetrating peptides was studied in vitro using human fibrosarcoma cells HT-1080. It was shown, that the binding of cell-penetrating peptide R7 - alone or combined with the peptide containing specific targeting motif NGR (Asn-Gly-Arg) - resulted in 3-fold decrease of Ce6 photoinduced activity as compared with that in nanoparticles without peptides (IC50 values were 0.7 µg/ml and 2.1 µg/ml, respectively). The NGR influence was unexpectedly low - less than 20% (IC50 1.7 µg/ml). This suggests the more importance of Ce6 cell penetration in this case, than of NGR-mediated targeting. The effect of inclusion of both peptides on the total cytotoxicity of Ce6 was minimal (10-16 times less than on the specific photoinduced activity). The obtained results - together with earlier shown effects on improvement of the pharmacokinetics of Ce6 in vivo after its embedding into phospholipid nanoparticles - indicate the prospects of using the obtained phospholipid nanoparticles system for photodynamic therapy.

[Prednisolone in phospholipid nanoparticles: prolonged circulation and increased antiinflammatory effect]. / Prednizolon v fosfolipidnykh nanochastitsakh: prolongirovannaia tsirkuliatsiia i povyshennoe protivovospalitel'noe deistvie.

Along with modern new drugs, many therapeutic schemes also include known effective drugs, particularly, glucocorticoids. One of the most distributed of them is prednisolone that has pronounced anti-inflammatory properties. Its disadvantage is short-term circulation, resulting in a number of side effects. For this reason the development of its more effective and safe formulations is carried out. We have obtained the formulation of prednisolone included in nanoparticles from soy phosphatidylcholine with an average diameter of 20 nm. With oral administration to rats and analysis by HPLC an increase in prednisolone maximal concentration in of plasma and the duration of circulation as compared with free drug administration were shown. The experiment with mice with conconavalin A induced inflammation was also carried out: conconavalin A was injected subplantary in an hour after oral administration of both prednisolone formulations in several doses. The index of the inflammatory reaction (determined by the edema degree) was suppressed more effectively in the case of prednisolone in nanoparticles. Maximal suppression (62.2% as compared with 49.6% for free prednisolone) was observed even at a minimal dose (2.5 mg/kg), at which the free drug did not act at all. The results indicate an increase in the efficiency of prednisolone included in phospholipid nanoparticles, that makes it possible to diminish its administered doses and thereby reduce the risk of side effects.

Effect of Cell-Penetrating Arginine Peptide on Interaction of Photosensitizer Chlorin e6 Incorporated into Phospholipid Nanoparticles with Tumor Cells.

We studied the possibility of increasing the efficiency of photodynamic therapy by improving delivery of photosensitizers chlorin e6 into tumor cells. Previous studies showed that incorporation of chlorin e6 onto phospholipid nanoparticles with a diameter <20 nm reduces its cytotoxicity due to accelerated elimination from organs [8]. A heptapeptide R7 synthesized and added to this combination promoted internalization of chlorin e6 into HepG2 cells in comparison with initial nanoparticles without peptide R7. The observed effect of peptide R7 can be explained by activation of endocytosis and/or macropinocytosis (bearing in mind the interaction of arginine with carboxyl groups of e6. The development of this transporting system is a promising trend in photodynamic therapy of cancer diseases.

Induction of lipid droplets in non-macrophage cells as well as macrophages by liposomes and exosomes.

It has been reported that phospholipid nanoparticles (PNPs) including liposomes and exosomes could efficiently induce lipid droplets (LDs) in macrophages. However, in non-macrophage cells, the effects of PNPs on the induction of LDs have not been thoroughly investigated. In this report, we directly compared non-macrophage and macrophage cell lines in terms of LD induction by various formulation of liposomes containing phosphatidylserine and exosomes. All non-macrophage cell lines as well as macrophage cell lines tested in this study showed evident LD induction in response to these PNPs, though the efficacy of LD induction in non-macrophage cell lines varied considerably. Our results suggest that LD formation is a common and crucial response to PNPs in mammalian cells not only in macrophages but also in non-macrophage cells.

[Improving of HDL capacity for macrophages cholesterol efflux after plasma incubation with phospholipid nanoparticles]. / Povyshenie sposobnosti lipoproteinov vysokoi plotnosti k vyvedeniiu kholesterina iz makrofagov pri inkubatsii plazmy s ul'tramalymi fosfolipidnymi chastitsami.

In connection with recent data about antiatherogenic importance of not only plasma HDL concentration, but of their cell cholesterol efflux capacity as well, the possibility of its correction by phospholipid (PL) nanoparticles was studied. Blood plasma was incubated with earlier elaborated PL nanoparticles emulsion with the particle diameter up to 30 nm, and HDL cholesterol efflux capacity of apo B-depleted plasma was studied. Using macrophages THP-1 preloaded 3H-cholesterol were used. The addition of incubated plasma supernatants with the elevated PL/apo A-1 ratio to cell media resulted in almost increase in two fold 3H-cholesterol efflux as compared with native HDL. The maximal efflux was observed at the PL/apo A-1 ratio of 1.06 as compared with native apo B-depleted plasma (the PL/apo A-1 ratio of 0.85). Results suggest possible usage of ultrasmall PL nanoparticles for regeneration of impaired antiatherogenic HDL functionality. This approach seems to be predominant compared with the usage of PL emulsions with detergent or apoprotein A1.

[Increase of antituberculosis efficiency of rifampicin embedded into phospholipid nanoparticles with sodium oleate]. / Povyshenie protivotuberkuleznogo deistviia rifampitsina pri vstraivanii v fosfolipidnye nanochastitsy c oleatom natriia.

The formulation of the antituberculosis drug rifampicin embedded into 20-30 nm nanoparticles from soy phosphatidylcholine and sodium oleate, is characterized by greater bioavailability as compared with free drug substance. In this study higher antituberculosis activity of this formulation was shown. Rifampicin in nanoparticles demonstrated more effective inhibition of M. tuberculosis H37Rv growth: minimal inhibiting concentration (MIC) was twice smaller than for free rifampicin. Administration of this preparation to mice with tuberculosis induced by M. tuberculosis Erdman revealed that after 6 weeks of oral administration the CUF value in lung was 22 times smaller for rifampicin in nanoparticles than for free drug (1.7 un. vs. 37.4 un.). The LD50 value in mice was two fold higher for rifampicin in nanoformulation.