Selenazolidines as novel organoselenium delivery agents.

Two new classes of selenazolidine-4(R)-carboxylic acids (2-oxo and 2-methyl-SCAs) were synthesized and characterized. Both were designed as latent forms of selenocysteine, intended to provide a chemically superior delivery form for selenium. The prodrugs may be clinically useful when selenium supplementation at supranutritional levels is indicated, such as in cancer chemoprevention.     

Albumin-based drug delivery as novel therapeutic approach for rheumatoid arthritis

We reported recently that albumin is a suitable drug carrier for targeted delivery of methotrexate (MTX) to tumors. Due to pathophysiological conditions in neoplastic tissue, high amounts of albumin accumulate in tumors and are metabolized by malignant cells. MTX, covalently coupled to human serum albumin (MTX-HSA) for cancer treatment, is currently being evaluated in phase II clinical trials. Because synovium of patients with rheumatoid arthritis (RA) shares various features observed also in tumors, albumin-based drug targeting of inflamed joints might be an attractive therapeutic approach. Therefore, the pharmacokinetics of albumin and MTX in a mouse model of arthritis was examined. Additionally, uptake of albumin by synovial fibroblasts of RA patients and the efficacy of MTX and MTX-HSA in arthritic mice were studied. The results show that when compared with MTX, significantly higher amounts of albumin accumulate in inflamed paws, and significantly lower amounts of albumin are found in the liver and the kidneys. The protein is metabolized by human synovial fibroblasts in vitro and in vivo. MTX-HSA was significantly more effective in suppression of the onset of arthritis in mice than was MTX. In conclusion, albumin appears to be a suitable drug carrier in RA, most likely due to effects on synovial fibroblasts, which might increase therapeutic efficacy and reduce side effects of MTX.     

Cationic porphyrins: novel delivery vehicles for antisense oligodeoxynucleotides.

Cationic porphyrins form stable complexes with oligodeoxynucleotides. To evaluate delivery, we used a 20mer phosphorothioate oligomer (Isis 3521) targeted to the 3'-untranslated region of the PKC-alpha mRNA, and complexed it with porphyrin. The expression of PKC-alpha protein and mRNA in T24 bladder carcinoma cells was reduced by approximately 80 +/- 10% at a concentration of oligomer of 3 microM, and 9 microM porphyrin. The expression of PKC-beta1, -delta and -straightepsilon isoforms was unaffected by this treatment, but elimination of PKC-zeta protein and mRNA were observed. However, treatment with the porphyrin complex of Isis 3522, an oligomer which is directed at the 5' coding region of the PKC-alpha mRNA, was equally effective as Isis 3521 with respect to PKC-alpha, but did not affect PKC-zeta protein or mRNA levels. Since Isis 3521 has an 11-base region of complementarity with the PKC-zeta mRNA, wheras Isis 3522 has only a 4-base region, the effect of Isis 3521 on PKC-zeta protein and mRNA expression may be due to irrelevant cleavage. Depending upon the desired application, this new strategy may offer several advantages over other methods of antisense oligodeoxynucleotide delivery including efficiency, stability, solubility, relatively low toxicity and serum compatibility. Porphyrins may thus be a potentially useful delivery vehicle for antisense therapeutics and/or target validation.     

pH-sensitive membrane peptides (pHLIPs) as a novel class of delivery agents

Abstract

Here we review a novel class of delivery vehicles based on pH-sensitive, moderately polar membrane peptides, which we call pH (Low) Insertion Peptides (pHLIPs), that target cells located in the acidic environment found in many diseased tissues, including tumours. Acidity targeting by pHLIPs is achieved as a result of helix formation and transmembrane insertion. In contrast to the earlier technologies based on cell-penetrating peptides, pHLIPs act as monomeric membrane-inserting peptides that translocate one terminus across a membrane into the cytoplasm, while the other terminus remains in the extracellular space, locating the peptide in the membrane lipid bilayer. Therefore pHLIP has a dual delivery capability: it can tether cargo molecules or nanoparticles to the surfaces of cells in diseased tissues and/or it can move a cell-impermeable cargo molecule across the membrane into the cytoplasm. The source of energy for moving polar molecules attached to pHLIP through the hydrophobic layer of a membrane bilayer is the membrane-associated folding of the polypeptide. A drop in pH leads to the protonation of negatively charged residues (Asp or Glu), which enhances peptide hydrophobicity, increasing the affinity of the peptide for the lipid bilayer and triggering peptide folding and subsequent membrane insertion. The process is accompanied by the release of energy that can be utilized to move cell-impermeable cargo across a membrane. That the mechanism is now understood, and that targeting of tumours in mice has been shown, suggest a number of future applications of the pHLIP technology in the diagnosis and treatment of disease.     

pH-sensitive membrane peptides (pHLIPs) as a novel class of delivery agents

Abstract Here we review a novel class of delivery vehicles based on pH-sensitive, moderately polar membrane peptides, which we call pH (Low) Insertion Peptides (pHLIPs), that target cells located in the acidic environment found in many diseased tissues, including tumours. Acidity targeting by pHLIPs is achieved as a result of helix formation and transmembrane insertion. In contrast to the earlier technologies based on cell-penetrating peptides, pHLIPs act as monomeric membrane-inserting peptides that translocate one terminus across a membrane into the cytoplasm, while the other terminus remains in the extracellular space, locating the peptide in the membrane lipid bilayer. Therefore pHLIP has a dual delivery capability: it can tether cargo molecules or nanoparticles to the surfaces of cells in diseased tissues and/or it can move a cell-impermeable cargo molecule across the membrane into the cytoplasm. The source of energy for moving polar molecules attached to pHLIP through the hydrophobic layer of a membrane bilayer is the membrane-associated folding of the polypeptide. A drop in pH leads to the protonation of negatively charged residues (Asp or Glu), which enhances peptide hydrophobicity, increasing the affinity of the peptide for the lipid bilayer and triggering peptide folding and subsequent membrane insertion. The process is accompanied by the release of energy that can be utilized to move cell-impermeable cargo across a membrane. That the mechanism is now understood, and that targeting of tumours in mice has been shown, suggest a number of future applications of the pHLIP technology in the diagnosis and treatment of disease.     

Benzoquinazoline derivatives as new agents affecting DNA processing

A new series of benzo[h]quinazoline and benzo[f]quinazoline derivatives was prepared and studied for the biological activity. The compounds carrying a dimethylaminoethyl side chain (6c, 8c and 12) inhibit cell growth. The ability to form a molecular complex with DNA and to interfere with topoII and topoI relaxation activity was evidenced for the most active 6c and 8c, along with the capacity to induce apoptosis on HeLa cells.     

Liposomes as delivery agents for medical imaging

Medical imaging requires an appropriate intensity of signal from the area of interest in order to differentiate certain structures from surrounding tissues, regardless of the modality used. In the majority of cases, contrast agents specific for each imaging modality are necessary to achieve a sufficiently intense signal. To facilitate the accumulation of contrast in the required zone, various microparticulates have been suggested as carriers for contrast agents. Among these carriers, liposomes - microscopic artificial phospholipid vesicles - draw special attention because of their easily controlled properties and useful pharmacological characteristics. This review will discuss how the advantages of liposomes have been used so far in the rapidly growing field of diagnostic medical imaging.     

7-O-Arylmethylgalangin as a novel scaffold for anti-HCV agents

In spite of potent antiviral activity, suboptimal physicochemical properties of aryl diketo acids (ADKs) necessitates modification of the core 1,3-diketo acid functionality into a novel scaffold. As the metal-binding affinity of the diketo acid is the key to the antiviral activity of ADKs, we anticipated 3,5-dihydroxy-4-oxo arrangement of galangin scaffold would serve as an excellent mimic for the diketo acid functionality. In this study, through synthesis and biological evaluation of various galangin derivatives, we have shown that the diketo acid functionality can be successfully replaced with the galangin scaffold by specific combination of the substituents to result in identification of a novel galangin derivative (3s) with anti-HCV activity (EC₅₀ = 0.9 μM) comparable to the ADK counterpart.     

Cationic lipophosphoramidates and lipophosphoguanidines are very efficient for in vivo DNA delivery

Two new families of cationic lipids were designed and synthesized for gene delivery, namely "lipophosphoramidates" and "lipophosphoguanidines", whose efficiency was noteworthy. The most efficient have an arsonium cation as the polar head, and the unsaturated lipidic tails (e.g. oleyl) gave the better in vivo results (mice lungs).     

Synthetic studies of cis-4-Amino-L-proline derivatives as novel lipid lowering agents

cis-4-Amino-L-proline derivatives 1 and 2 derived from quinazolinone and pyrazolo pyrimidone respectively were designed as novel lipid lowering agents. A preliminary in vivo screening indicates that 1b and 2a have moderate triglyceride lowering activity.     

Polyhydroxylated azepanes as new motifs for DNA minor groove binding agents.

The synthesis of 1,3-bis-[3,4,5,6-tetrahydroxyazepane-N-p-phenoxy] and 1,3-bis-[3,4,5,6-tetrahydroxyazepane-N-p-benzyloxy] propanes is reported. These compounds have been prepared to investigate the potential of incorporating iminosugars as useful recognition elements in DNA minor groove binding agents. The compounds were shown to have very moderate binding affinities for DNA in thermal denaturation and ethidium bromide displacement assays when compared with propamidine. They were also found to possess some in vitro anticancer activity that did not correlate with their DNA binding affinity.     

Dodecaborate lipid liposomes as new vehicles for boron delivery system of neutron capture therapy

closo-Dodecaborate lipid liposomes were developed as new vehicles for boron delivery system (BDS) of neutron capture therapy. The current approach is unique because the liposome shell itself possesses cytocidal potential in combination with neutron irradiation. The liposomes composed of closo-dodecaborate lipids DSBL and DPBL displayed high cytotoxicity with thermal neutron irradiation. The closo-dodecaborate lipid liposomes were taken up into the cytoplasm by endocytosis without degradation of the liposomes. Boron concentration of 22.7 ppm in tumor was achieved by injection with DSBL-25% PEG liposomes at 20 mg B/kg. Promising BNCT effects were observed in the mice injected with DSBL-25% PEG liposomes: the tumor growth was significantly suppressed after thermal neutron irradiation (1.8 × 10¹² neutrons/cm²).     

Hybrid of niosomes and bio-synthesized selenium nanoparticles as a novel approach in drug delivery for cancer treatment

Molecular Biology Reports - The current study intends to investigate a novel drug delivery system (DDS) based on niosomes structure (NISM) and bovine serum albumin (BSA) which was...     

Glyco-optimization of aminoglycosides: new aminoglycosides as novel anti-infective agents

Glyco-optimization (OPopS) of aminoglycosides has been performed by replacing the existing sugar moiety with a variety of sugar derivatives. Glycosylation of the 6-position of nebramine provided a library of novel 4,6-linked aminoglycosides (AMGs). Among them, compounds 8b,g,i,l, and 8u with 2"-amino, 2",3"-diamino, 2",4"-diamino, 3",4"-diamino, 3"-amino groups, respectively, showed significant antimicrobial activity against Gram-(+) and -(-) bacteria. Several were particularly potent against Pseudomonus aeruginosa with MICs in the 1-2 microg/mL range.     

Bioactive glasses as delivery systems for antimicrobial agents

Most biomaterial‐associated infections are caused by opportunistic pathogens and bacteria that are regularly found within the microflora of the implant site. In addition, a biomaterial implant or device remains at risk of infection by hematogenous spread of bacteria disseminated from infections elsewhere in the body or from infected peri‐implant tissue in revision surgery. The resulting infections are frequently accompanied by patient morbidity and discomfort and can lead to surgical replacement of the implant after lengthy, unsuccessful attempts to mitigate infections with antibiotic treatments. Therefore, extensive study is aiming to find new infection‐resistant antimicrobial biomaterials and coatings for implants and devices to effectively reduce the incidence of biomaterial‐associated infections. An overview of the in vitro and in vivo antimicrobial efficacies of the numerous biomaterials currently available is beyond the scope of this review. Herein, we provide a comprehensive review of bioactive glasses as biomaterial delivery systems for antimicrobial agents.     

Liposomal drug delivery, a novel approach: PLARosomes

Almost from the time of their rediscovery in the 60's and the demonstration of their entrapment potential, liposomal vesicles have drawn attention of researchers as potential carriers of various bioactive molecules that could be used for therapeutic applications in humans and animals. Several commercial liposome-based drugs have already been discovered, registered and introduced with great success on the pharmaceutical market. However, further studies, focusing on the elaboration of more efficient and stable amphiphile-based vesicular (or non-viral) drug carriers are still under investigation. In this review we present the achievements of our group in this field. We have discovered that natural amphiphilic dihydroxyphenols and their semisynthetic derivatives are promising additives to liposomal lipid compositions. The presence of these compounds in lipid composition enhances liposomal drug encapsulation, reduces the amount of the lipid carrier necessary for efficient entrapment of anthracycline drugs by a factor of two, stabilizes liposomal formulation of the drug (both in suspension and in a lyophilized powder), does not influence liposomal fate in the blood circulation system and benefits from other biological activities of their resorcinolic lipid modifiers.