We have been working on liposomes and immunoliposomes for drug delivery. Current activities are focused in the development of non-viral vectors for gene therapy and receptor mediated drug targeting.
Targeting siRNA to tumor cells
We have developed self-assembled nanoparticles covalently attached with either tamoxifen or anisamide ligand that binds to surface estrogen or sigma receptor, respectively, over-expressed in the human tumor cells. The target-specific nanoparticles can be used to deliver siRNA and other oligonucleotides to down-regulate target oncogenes, resulting in the apoptosis and/or the chemosensitization of the tumor cells. When the anisamide-targeted formulation was intravenously injected into tumor-bearing mice in a xenograft model, 70-80% of the injected siRNA per gram of tissue accumulated in the tumor resulting in nearly total silencing of the target oncogenes through out the entire tumor. Such unprecedented high efficiency of drug delivery is a very encouraging result. We have also delivered therapeutic siRNA to melanoma tumor cells metastasized in the lung and showed significant reduction in the tumor load in the treated animals.
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Nanoparticle vectors evading reticuloendothelial system (RES)
We have developed a core/membrane type nanoparticle, called LPD, for delivery of plasmid DNA, antisense oligonucleotides and siRNA. The membrane lipid bilayer interacts with the core by charge-charge interaction and is hence a supported bilayer with enhanced stability. It can be modified with a high level (~10 mol%) of polyethylene glycol (PEG). The highly PEGylated LPD nanoparticles showed very low liver and spleen uptake due to the presence of a brush layer of PEG protecting and shielding the particle surface. The RES evading nanoparticles showed unusually high uptake by the tumor due to the enhanced permeability and retention (EPR) effect.
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 Overcoming multidrug resistance in cancer
Doxorubicin can be co-formulated with siRNA in LPD and co-delivered to multidrug resistant cancer cells. We have discovered that c-myc siRNA delivered to NCI/Adr tumor in nude mice not only silenced c-myc expression, it also down-regulated the expression of p-glycoprotein which is responsible for the MDR phenotype. Furthermore, a cationic lipid synthesized in the lab, DSAA, could also down-regulate p-Gp via enhanced reactive oxygen species (ROS). When DSAA is used as a formulation lipid in LPD, the co-delivered doxorubicin was particularly active in inhibiting tumor growth.
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 Novel nanoparticles with enhanced cargo escape from the endosome
To enhance the de-assembly of the nanoparticle in the acidic endosome, the core of the nanoparticles has been replaced with calcium phosphate nano-precipitates. The resulting nanoparticles, named LCP, are about 50-fold more effective in delivering siRNA than LPD nanoparticles. The newest version, LCP-II, is small (about 30-35 nm) and contains a hollow CaP core.
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A series of photos and slides developed throughout the course of Dr. Huang's research at University of Tennessee and University of Pittsburgh.
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