Combination radiofrequency ablation with intratumoral liposomal doxorubicin: effect on drug accumulation and coagulation in multiple tissues and tumor types in animals.

Purpose: To determine whether use of radiofrequency (RF) ablation combined with intravenously (IV) administered liposomal doxorubicin, as compared with use of RF ablation or doxorubicin alone, facilitates increased tissue coagulation and interstitial drug accumulation in animal models.

Materials And Methods: The institutional animal care and use committee approved this study. In experiment 1, multiple canine sarcomas were implanted in seven mildly immunosuppressed dogs and grown to a mean diameter of 4.

Polymeric micelles for delivery of poorly soluble drugs: preparation and anticancer activity in vitro of paclitaxel incorporated into mixed micelles based on poly(ethylene glycol)-lipid conjugate and positively charged lipids.

Paclitaxel-loaded mixed polymeric micelles consisting of poly(ethylene glycol)-distearoyl phosphoethanolamine conjugates (PEG-PE), solid triglycerides (ST), and cationic Lipofectin lipids (LL) have been prepared. Micelles with the optimized composition (PEG-PE/ST/LL/paclitaxel = 12/12/2/1 by weight) had an average micelle size of about 100 nm, and zeta-potential of about -6 mV. Micelles were stable and did not release paclitaxel when stored at 4 degree C in the darkness (just 2.

Interaction of a novel peptoid enhancer--arginine oligomer with bovine submaxillary mucin.

Aim: To determine the thermodynamics of binding reaction of arginine oligomer (R8) to bovine submaxillary mucin (BSM) in order to provide the foundation for understanding the influence of mucin on transport of macromolecules through mucosa mediated by arginine oligomer.

Methods: Ultracentrifugation sedimentation was employed to investigate the interaction of BSM-R8. The mixtures of R8 with variable concentration and constant volume of BSM were placed on a shaker under oscillation at 25 degrees C to achieve equilibriums of binding reaction, and then centrifuged.

Intracellular delivery of large molecules and small particles by cell-penetrating proteins and peptides.

Cell-penetrating peptides (CPPs) have been used to overcome the lipophilic barrier of the cellular membranes and deliver large molecules and even small particles inside the cell for their biological actions. CPPs are being used to deliver inside cell a large variety of cargoes such as proteins, DNA, antibodies, contrast (imaging) agents, toxins, and nanoparticular drug carriers including liposomes. In this paper, we have reviewed the delivery of different molecules and particles mediated by TAT, Antp, VP22, and other CPPs as well as potential applications of these delivery systems in different areas of vaccine development, cancer immunotherapy, gene delivery, and cellular imaging.

Recent advances with liposomes as pharmaceutical carriers.

Liposomes - microscopic phospholipid bubbles with a bilayered membrane structure - have received a lot of attention during the past 30 years as pharmaceutical carriers of great potential. More recently, many new developments have been seen in the area of liposomal drugs - from clinically approved products to new experimental applications, with gene delivery and cancer therapy still being the principal areas of interest. For further successful development of this field, promising trends must be identified and exploited, albeit with a clear understanding of the limitations of these approaches.

Fluorescence microscopy to follow the targeting of liposomes and micelles to cells and their intracellular fate.

Fluorescence microscopy may provide important information regarding interactions between nanoparticulate drugs carriers, such as liposomes and micelles, with target cells as well as their intracellular fate. Current paper describes various applications of fluorescence microscopy to investigate specific targeting of antibody-modified drug carriers to cancer cells. The enhanced antibody-mediated targeting of drug-loaded immunomicelles confirmed by fluorescence microscopy resulted in enhanced cancer cell killing compared to free drug or drug-loaded nontargeted micelles.

Tumor-targeted liposomes: doxorubicin-loaded long-circulating liposomes modified with anti-cancer antibody.

Commercially available doxorubicin-loaded long-circulating liposomes (Doxil, Alza Pharmaceuticals) were modified with the monoclonal nucleosome (NS)-specific 2C5 antibody (mAb 2C5) that recognizes a broad variety of tumors via the tumor cell surface-bound NSs. For incorporation into liposomes, mAb 2C5 was modified with poly(ethylene glycol)-phosphatidyl ethanolamine conjugate (PEG-PE) with the free PEG terminus activated with the p-nitrophenylcarbonyl group (pNP-PEG-PE). Derivatives of mAb 2C5 containing a variable number of PEG-PE residues (10-32) per protein molecule were prepared with a reasonably good preservation of the antibody specific activity even at the highest degree of modification.

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.

Micelles from lipid derivatives of water-soluble polymers as delivery systems for poorly soluble drugs.

Polymeric micelles have a whole set of unique characteristics, which make them very promising drug carriers, in particular, for poorly soluble drugs. Our review article focuses on micelles prepared from conjugates of water-soluble polymers, such as polyethylene glycol (PEG) or polyvinyl pyrrolidone (PVP), with phospholipids or long-chain fatty acids. The preparation of micelles from certain polymer-lipid conjugates and the loading of these micelles with various poorly soluble anticancer agents are discussed.

Preparation and in vitro synergistic anticancer effect of vitamin K3 and 1,8-diazabicyclo[5,4,0]undec-7-ene in poly(ethylene glycol)-diacyllipid micelles.

Polymeric micelles consisting of poly(ethylene glycol)-distearoyl phosphoethanolamine conjugates (PEG-DSPE) loaded with Vitamin K3 (VK3) to 0.2 mg of drug/mg of carrier and with 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) to 0.06 mg of drug/mg of carrier were prepared.

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.

Increased accumulation of PEG-PE micelles in the area of experimental myocardial infarction in rabbits.

Micelles prepared from polyethyleneglycol/phosphatidyl-ethanolamine conjugates (PEG-PE) with a size of 7-20 nm and zeta-potential of approximately -18 mV were administered i.v. to rabbits with experimental myocardial infarctions.

Radiofrequency thermal ablation sharply increases intratumoral liposomal doxorubicin accumulation and tumor coagulation.

Combining radiofrequency (RF) ablation with i.v. liposomal doxorubicin (Doxil) increases intratumoral doxorubicin accumulation and tumor destruction.

DQAsome-mediated delivery of plasmid DNA toward mitochondria in living cells.

DQAsomes are mitochondriotropic cationic 'bola-lipid'-based vesicles, which have been developed by us for the transport of drugs and DNA to mitochondria in living cells. This has made direct mitochondrial gene therapy feasible for the very first time. Our strategy for the delivery of DNA into the matrix of mitochondria is based upon the DQAsomal transport of a DNA-signal peptide conjugate to mitochondria, the selective liberation of this conjugate from DQAsomes at the mitochondrial membrane followed by DNA uptake via the mitochondrial protein import machinery.

In vivo biodistribution of erythrocytes and polyethyleneglycol-phosphatidylethanolamine micelles carrying the antitumour agent dequalinium.

Dequalinium (DQA), a lipophilic drug with anti-cancer activity has been incorporated into mouse red blood cells (DQA-RBCs) and polyethylene glycol phosphatidylethanolamine micelles (DQA-PEG-PE-micelles) in order to overcome the drug's solubility problems and to make it suitable for in vivo applications. The incorporation of DQA into erythrocytes, the release of DQA from RBCs in the presence of autologous plasma and the biodistribution of 51Cr-DQA-RBCs and 111In-DQA-PEG-PE micelles in mice has been studied. Under optimal conditions, up to 84.

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.

Antiactin-targeted immunoliposomes ameliorate tissue plasminogen activator-induced hemorrhage after focal embolic stroke.

Thrombolytic stroke therapy with tissue plasminogen activator (tPA) is limited by serious risks of intracerebral hemorrhage. In this study, the authors show that a novel antiactin-targeted immunoliposome significantly reduced tPA-induced hemorrhage in an established rat model of embolic focal stroke. Spontaneously hypertensive rats were subjected to focal ischemia using homologous blood clot emboli.

Intracellular targets for DNA delivery: nuclei and mitochondria.

All discussions on the intracellular delivery of DNA are based on a seemingly evident assumption that the key task is to bring the intact DNA into the cell cytoplasmic compartment, and then the DNA will find its way to a right place. The nuclear genome is usually considered to be this "right place." However, until recently, in numerous experiments on the intracellular DNA delivery, it has been almost completely neglected that cells contain another genome, the mitochondrial one.

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.

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.

Cell transfection in vitro and in vivo with nontoxic TAT peptide-liposome-DNA complexes.

Liposomes modified with TAT peptide (TATp-liposomes) showed fast and efficient translocation into the cell cytoplasm with subsequent migration into the perinuclear zone. TATp-liposomes containing a small quantity ( View Article and Find Full Text PDF

Cationic charge determines the distribution of liposomes between the vascular and extravascular compartments of tumors.

Tumor vessels possess unique physiological features that might be exploited for improving drug delivery. In the present study, we investigate the possibility of modifying polyethylene glycol-ylated liposome cationic charge of polyethylene glycol coated liposomes to optimize delivery to tumor vessels using biodistribution studies and intravital microscopy. The majority of liposomes accumulated in the liver, and increasing charge resulted in lower retention in the spleen and blood.

Polyethylene glycol-diacyllipid micelles demonstrate increased acculumation in subcutaneous tumors in mice.

Purpose: The purpose of this work is to study the potential of micelles prepared from amphiphilic polyethelene glycol/phosphatidylethanolamine (PEG-PE) conjugates as a particulate drug delivery system capable of accumulation in tumors via the enhanced permeability and retention (EPR) effect.

Methods: Micelles were prepared from PEGs of different molecular lengths conjugated with PE. The micelles were characterized by fluorescence-based critical micellization concentration (CMC) measure ments, dynamic light scattering, and HPLC.

Radio-frequency ablation increases intratumoral liposomal doxorubicin accumulation in a rat breast tumor model.

Purpose: To determine whether intratumoral accumulation of liposomal doxorubicin or free unencapsulated doxorubicin is increased when combined with radio-frequency (RF) ablation.

Materials And Methods: Two 1.2-1.