Home Page Researchers Avi Domb

Avi Domb

Department of Pharmaceutics
School of Pharmacology, Faculty of Medicine
The Hebrew University, Jerusalem 91120, Israel
Tel: +972-2-6757573; Fax: +972-2-6757629
E-mail:avid@ekmd.huji.ac.il
Website:http://pharmacy.huji.ac.il/eng/staff_win.asp?id=49&type=2

During this year we have investigated the solid lipid nanoparticulate system (Liposphere) for improved oral bioavailability of drugs with low oral bioavailability and ocular formulations for cyclosporine for treating ocular inflammation. The safety and application of dextran-spermine polycations for gene delivery has been tested in animals for treating colorectal cancer.

Lipospheres are a drug encapsulation system composed of water dispersible solid microparticles of particle size between 0.01 and 100 _m in diameter with a solid hydrophobic lipid core stabilized by a layer of phospholipid molecules embedded in their surface. The bioactive compound is dissolved or dispersed in the solid lipid matrix of the internal core. Since lipospheres were introduced in the beginning of the 1990s, they have been used for the delivery of multiple types of drugs by various routes of administration. Later, a self-assembling pro-nano lipospheres (PNL) encapsulation system was developed for oral drug delivery. Lipospheres have several advantages over other delivery systems, such as better physical stability, low cost of ingredients, ease of preparation and scale-up, high dispersibility in an aqueous medium, high entrapment of hydrophobic drugs, controlled particle size, and extended release of entrapped drug after administration, from a few hours to several days.

The present study was aimed at characterizing and evaluating pro-dispersion liposphere formulation for Cyclosporine-A (CsA). The delivery system consisted of a solid fat and an amphiphilic solvent as the major components. The in-vitro characteristics of such formulations have become more complex. Various components? interactions and inactive ingredients may result in different types of dispersions and having different qualities and properties. In the recent years, it has also become clear that different galenic formulations may have different impacts on the behavior, stability and pharmacokinetics of CsA. Various tests, using various lipid cores and various solvents containing the lipospheres, were performed to characterize the formulations. Conclusion: The liposphere formulation was found to be suitable for obtaining a stable CsA oral formulation. The physical characteristics demonstrated that the clear solution upon contact with water provides a dispersion having various particle sizes (nano to micron size) and its nature is influenced by the type of solid-fat and solvent used.

Cyclosporin A (CsA) is a widely used anti-inflammatory agent for the management of dry eye disease, and is available commercially as ophthalmic emulsion formulation (RESTASIS®). For increasing efficacy, and for reducing local toxicity including irritation to eyes, CsA nanosphere (CsA-NS) formulation was prepared and evaluated, in this work. CsA-NS formulation was prepared in a pre-concentrate form, which is a homogeneous solution of a CsA in a mixture of surfactants, lipids and solvents and provides nanosphere dispersion when added to aqueous medium. CsA-NS formulation was characterized and adjusted for particle size, pH, and osmolarity, suitable for ophthalmic administration. Thereafter, CsA-NS formulation was evaluated for parameters like irritation to eyes and penetrability of CsA in the rabbit eyes. Results obtained demonstrated that proposed CsA-NS formulation causes less irritation in rabbit eyes, with nearly same CsA penetration in the rabbit eyes in comparison to marketed emulsion formulation.

Magnetic iron oxide nanoparticles surface covered with oleic acid layer followed by second layer of hydrophobized oxidized dextran aldehyde were prepared and tested for physico-chemical properties and ligand and cell-specific binding. Here we demonstrate that oleic acid-iron nanoparticles coated with additional layer of hydrophobized oxidized dextran were dispersible in buffer solutions and posses surface aldehyde active groups available for farther binding of ligands or markers via imine or amine bond formation. Hydrophobized dextrans were synthesized by periodate oxidation and conjugation of various alkanolamines to oxidized dextran by imination. Physico-chemical properties, as magnetization, magnetite concentration and particle diameter of the prepared magnetic samples are reported. The biotin-binding protein, Neutravidin, was coupled to the particle surface by a simple reductive amination procedure and the particles used for specific cell separation with high specificity.

Liver metastasis is the main cause of mortality related to colorectal cancer. CXCR4 is necessary for the outgrowth of colon cancer micrometastases. In oncology, it has been demonstrated that several human tumors release lactate dehydrogenase (LDH) into the circulation. CXCR4 gene expression and serum LDH levels are often increased in patients with colorectal cancer. Despite technologic advances in cancer therapy, five-year overall survival is still around 50%. Therefore, better treatment needs to be developed. RNA interference (RNAi) is a modern and powerful tool for inhibition of gene expression. However, the rate-limiting step in this technology is effective delivery of RNAi agents. We have investigated a novel strategy of CXCR4 siRNA therapy and its effect on serum LDH levels in a BALB/C mouse model of colorectal cancer metastasis to the liver. Hepatic metastasis was established by injecting a CT26.WT mouse colon carcinoma cell line via the tail vein. Our results demonstrated that CXCR4 siRNA/dextran-spermine nanoparticles achieved high silencing efficiency with low toxicity. Favorable localization of the nanoparticles was confirmed with CXCR4 gene expression in the liver, that was correlated with serum LDH levels. More research will be needed to determine the effect of CXCR4 silencing on serum LDH levels, which may be a useful marker for predicting liver metastasis in colorectal cancer.

Specific topics related to Nanoscience and Nanotechnology:

  • Improved bioavailability of drugs using lipid nanoparticles
  • Surface crystallization of drugs
  • Antimicrobial nanoparticles

List of publications in Nanoscience and Nanotechnology (2011-2012):

  • Shalini Verma, Abraham J. Domb and Neeraj Kuma, Nanomaterials for regenerative medicine, Nanomedicine (Lond). 2011 Jan;6(1):157-81.
  • Yudovin-Farber, I.; Eliyahu, H.; Domb, A. J., Synthesis of cationic polysaccharides and use for in vitro transfection. Cold Spring Harb Protoc 2011, pdb prot5553.
  • Hosseinkhani H., Hosseinkhani N., Yi-Ru Chen, Subramani K., Domb A.J., Innovative technology of engineering magnetic DNA nanoparticles for gene therapy, Int. J. Nanotechnol. In press
  • Abedini F, Hosseinkhani H, Ismail M., Yi-Ru Chen, Omar Abdul Rahman, Pei Pei Ch., Domb A.J., In vitro intracellular trafficking of biodegradable nanoparticles dextran-spermine in cancer cell lines, Int. J. Nanotechnol. In press.
  • Abedini F, Hosseinkhani H, Ismail M., Yi-Ru Chen, Omar Abdul Rahman, Pei Pei Ch., Domb A.J. Effects of CXCR4 siRNA/dextran-spermine nanoparticles on CXCR4 expression and serum LDH levels in a mouse model of colorectal cancer metastesis to the liver, Cancer Management and Research (in press).
  • Elgart A, Cherniakova I, Aldouby Y., Domb AJ, Hoffman A, Lipospheres and Pro-Nano Lipospheres for Delivery of Poorly Water Soluble Compounds, Chem. Phys. Lipids, (2012), 165(4), 438-453.
  • Avramoff, A. Khan, W., Ezra, A., Elgart, A., Hoffman, A., Domb, AJ, Cyclosporin pro-dispersion liposphere formulation, J. Contr. Rel. (2012), 160(2), 401-406.
  • Levy Y., Khan W., Farah S., and Domb AJ, Surface Crystallization of Rapamycin on stents using a Temperature Induced Process, Langmuir, 2012, 28(15), 6207?6210.
  • Khan W., Farah S. and Domb AJ, Drug eluting stents: Developments and current status, Journal of Controlled Release, 2012, doi: 10.1016/j.jconrel.2012.02.010.
  • S Kagan, D Ickowicz, M Shmuel, Y Altschuler, E Sionov, M Pitusi, A Weiss, Shimon Farber, Abraham J Domb, Itzhack Polacheck, Toxicity Mechanisms of Amphotericin B and Its Neutralization by Conjugation with Arabinogalactan, Antimicrob. Agents and Chemother., published 8. 2012.
  • W Khan, YH Aldouby, A Avramoff, AJ Domb, Cyclosporin Nanosphere Formulation for Ophthalmic Administration, Int. J. Pharmaceutics, published 9. 2012

Patents and patents utilization (2011-2012)

Applied patents:
  • 20100260703 INJECTABLE BIODEGRADABLE POLYMER COMPOSITIONS FOR SOFT TISSUE REPAIR AND AUGMENTATION
  • 20100247644 ADHESIVE COMPOSITIONS FOR THE TREATMENT OF XEROSTOMIA
  • 20100243550 GRAVITATIONAL FILTER AND LIQUID PURIFICATION DEVICE
  • 20100215733 DEVICE AND METHOD FOR REDUCING CALORIE INTAKE
  • 20100196470 DEVICE AND METHOD FOR REDUCING CALORIE INTAKE
Approved patents:
  • 7,749,539 Polymeric formulations for drug delivery
  • 7,732,404 Pro-nanodispersion for the delivery of cyclosporin
  • 7,297,347 Polyanhydrides
  • 7,026,290 Dispersible concentrate for the delivery of cyclosprin
  • 7,001,891 Biodegradable polycation composition for delivery of an anionic macromolecule

Cooperation with industries and defense projects (2011-2012)

Four projects with Industry by direct agreements through Yissum.

Success stories

Strauss Water on the development of new water purification filters

Cooperation with other researchers/universities in Israel:

Within Hebrew University:

  • Prof. Amnon Hoffman
  • Prof. Itzhak Polachek
  • Dr. Nurit Beyth
  • Prof. Kobi Golenser

With other universities:

  • Prof. Michael Gozin, Tel Aviv Univ
  • Dr. Shai Sela, Ichilov, Tel Aviv Univ
  • Dr. David Stepensky, Ben Gurion Univ

Research grants

  • ISF ? surface crystallization of bioactive agents
  • US army/Indiana Univ. ? Nanoparticles for nasal delivery of TRH

Students, postdocs and researchers (include those graduated in 2009-2010):

Postdocs: Dr. Wahid Khan from india
Ph.D. students: Shady Farah, Oren Mizrahi, Tomer Sinai, Diana Ickowitz
M.Sc students: Moran Haim-Zada, Ester Abeto, Hodaya Shadmon, Michael Braginsky, Sofia Luria.

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