Anatoly N. Lukyanov

Immunomicelles: Targeted pharmaceutical carriers for poorly soluble drugs

To prepare immunomicelles, new targeted carriers for poorly soluble pharmaceuticals, a procedure has been developed to chemically attach mAbs to reactive groups incorporated into the corona of polymeric micelles made of polyethylene glycol–phosphatidylethanolamine conjugates. Micelle-attached antibodies retained their ability to specifically interact with their antigens. Immunomicelles with attached antitumor mAb 2C5 effectively recognized and bound various cancer cells in vitro and showed an increased accumulation in experimental tumors in mice when compared with nontargeted micelles. Intravenous administration of tumor-specific 2C5 immunomicelles loaded with a sparingly soluble anticancer agent, taxol, into experimental mice bearing Lewis lung carcinoma resulted in an increased accumulation of taxol in the tumor compared with free taxol or taxol in nontargeted micelles and in enhanced tumor growth inhibition. This family of pharmaceutical carriers can be used for the solubilization and enhanced delivery of poorly soluble drugs to various pathological sites in the body.

Peptide and protein drug delivery to and into tumors: challenges and solutions.

The potential of peptide and protein anticancer agents has yet to be realized owing to the many unresolved problems concerning their delivery to the site of a tumor and into tumor cells. However, our understanding of the mechanisms underlying the biological fate and biodistribution of protein and peptide drugs has advanced to the stage where methods that use or influence these mechanisms are now available. There are different approaches that can improve the stability, longevity and targeting of peptides and proteins in the body, such as their modification with various soluble polymers, incorporation into microparticular drug carriers, enhanced permeability and retention effect-based tumor targeting and the use of targeting moieties. Furthermore, new approaches to intracellular drug delivery, including the use of transduction proteins and peptides, are being developed. These advances promise the delivery of a new generation of anticancer drugs.

Micelles from polyethylene glycol/phosphatidylethanolamine conjugates for tumor drug delivery.

Micelles prepared from polyethylene glycols of various lengths conjugated with phosphatidylethanolamine (PEG-PE) were loaded with various poorly soluble anticancer agents. PEG-PE micelles selectively accumulated in Lewis lung carcinoma (LLC) tumors implanted in mice. Modification of the micelles with tumor specific antibodies further enhanced the efficiency of tumor accumulation.

Improving microcirculation is more effective than substitution of red blood cells to correct metabolic disorder in experimental hemorrhagic shock.

Microcirculatory perfusion deficits and impaired tissue oxygenation in nonvital organs frequently occur after hemorrhage and they contribute to potentially lethal complications. The aim of this study was to test the influence of colloid osmotic pressure, viscosity, and red blood cell (RBC) content of the resuscitative fluid on metabolic disorder, perfusion, and oxygenation in peripheral tissues. Awake hamsters were subjected to hemorrhage of 50% and were resuscitated with 25% of blood volume with solutions containing 6% pegylated bovine albumin only (PEG-BSA 0) and 6% PEG-BSA mixed with autologous RBCs to reach 4 g/dL (PEG-BSA 4) and 8 g/dL (PEG-BSA 8) of hemoglobin. PEG-BSA had a viscosity of 4.2 cP and a COP of 116 mmHg. Microhemodynamics and tissue pO2 were assessed in the hamster chamber window preparation with intravital microscopy. Arterial base excess tended to be lower than baseline for PEG-BSA 0 and PEG-BSA 4 (ns), whereas base deficit remained significantly decreased for PEG-BSA 8 (P < 0.05 vs. baseline). Oxygen extraction was 91% ± 2% of the oxygen delivery for PEG-BSA 0 compared with 85% ± 2% for PEG-BSA 8 (P < 0.05). Functional capillary density was 61%, 47%, and 45% for PEG-BSA 0 (P < 0.05 vs. other groups), PEG-BSA 4 and PEG-BSA 8, respectively. We conclude that arterial base excess and oxygen extraction ratio in the tissue was better restored if a higher fraction of PEG-BSA and less RBCs were infused. This was attributed to a more homogeneous distribution of oxygen, as reflected by functional capillary density. Our results suggest that the transfusion trigger in hemorrhagic shock may be shifted toward lower hemoglobin concentrations if highly viscous and oncotic solutions are used.

PEGylated dextran as long-circulating pharmaceutical carrier

Dextran-polyethylene glycol (PEG) conjugates were synthesized by activating dextran hydroxy groups with carbonyldiimidazole, introducing amino groups by attaching ethylenediamine, and reacting amino groups with a succinimidyl-activated derivative of PEG. Conjugates with an average of 12 and 21 PEG (5 kDa) residues per single dextran (73 kDa) molecule were prepared. These conjugates have circulation half-lives of 5.3 h and 7.0 h, respectively, compared to 4.0 h for non-PEGylated dextran. The modification of dextran with PEG inhibits the uptake of polymer by the major organ of the reticuloendothelial system, the liver. Dextran-PEG conjugates may represent a convenient platform for long-circulating pharmaceutical preparations.

Autoclaving of liposomes.

The attempt was made to study liposome stability and oxidation under the autoclaving conditions. It was shown that after the preliminary air removal from a liposome sample there was no lipid oxidation (malonaldehyde bis(dimethyl acetate) was used as a control) and liposome content leakage during autoclaving. Liposomes with entrapped Intal remain completely intact after autoclaving for 15 min at 120 degrees C.