Fred Eshelman Distinguished Professor
Eshelman School of Pharmacy
Area of Interest
Huang’s research has been in the area of gene therapy and targeted drug delivery. He pioneered the liposome non-viral vector and has designed and manufactured the cationic lipid vector for the first non-viral clinical trial in 1992. He was also the first to publish the activity of polyethylene glycol (PEG) in prolonging the circulation time of liposomes. His current work centers on nanoparticle vectors for gene transfer in tumors and the liver. He also continues research in establishing a ligand targeted delivery system for cDNA, mRNA, siRNA, proteins, and peptides for tumor growth inhibition and for vaccines in treating cancer and infected diseases.
Delivering siRNA for cancer therapy
1. LPD nanoparticles: Two types of LPD nanoparticles have been designed and manufactured. Although both contain a DNA/siRNA/protamine core, LPD-I contains a cationic and LPD-II an anionic lipid membrane. Both can be surface modified by grafting a thick polyethylene glycol (PEG) brush to reduce protein adsorption and opsonization. Very high (~50% intravenously injected dose) level of tumor accumulation and very low level of liver and spleen uptake of the nanoparticles were observed. Upon three daily injections of the formulated siRNA, the target gene in the entire tumor was completely silenced. Since doxorubicin (Dox) can intercalate into dsDNA, we have included Dox/DNA complex in the LPD formulations such that both siRNA and Dox were efficiently delivered to the tumor cells to enhance the therapeutic activity. Several novel cationic lipids have been designed and synthesized which showed activities to down-regulate P-gp in the drug resistant cancer cells. When these lipids were used to formulate siRNA in LPD-I, the Dox/siRNA combination showed a potent therapeutic activity against the drug resistant tumor. Similarly, we have discovered that c-myc siRNA could down-regulate both c-myc and P-gp. The combination of Dox and c-myc siRNA formulated in LPD-II also showed potent inhibition of the drug resistant tumor in a xenograft model. Project supported by NIH grant CA129835.
2. LCP nanoparticles: The core of the nanoparticle of LCP contains a calcium phosphate (CaP) precipitate which dissolves rapidly in acidic pH. Like LPD, there are also two versions of LCP. LCP-I contains a cationic and LCP-II a neutral or anionic lipid membrane. Both can be PEGylated and targeted with a specific ligand for tumor cell uptake. Unlike LPD, LCP de-assembles in the endosome to release the cargo. Due to osmotic swelling of the endosome, siRNA is efficiently released into the cytoplasm of the tumor cell, resulting in an efficient target silencing. LCP can also carry chemotherapeutic drugs to be co-delivered with siRNA. Project supported by NIH grants CA149363.
Peptide cancer vaccine
We have discovered that cationic lipid DOTAP can activate dendritic cells without producing toxic TNF-α. Since DOTAP liposome can also encapsulate peptide antigens, a simple vaccine which contains only two components (a peptide and a lipid) has been developed to immunize the host. We have used a cervical cancer model to demonstrate the therapeutic activity of the vaccine. A peptide, which is the major epitope of the E7 oncoprotein of HPV and formulated in DOTAP liposomes, showed tumor growth inhibition activity after subcutaneous administration. E7-specific CTL activity was also observed after vaccination. Interestingly, only the R-DOTAP, but not the S-isomer, showed anti-tumor activity. We are currently studying the molecular recognition of the cationic lipid. Project supported by NIH grant CA129421.
Awards and Honors
- Alec D Bangham MD FRS Achievement Award, Liposome Research Days conference, Hsin-Chu, Taiwan, 2004
- Elected member of the Advisory Board, American Society of Gene Therapy, 2006
- Plenary speaker, annual meeting of The Pharmaceutical Society of Taiwan, Taiwan, 2007
- Plenary speaker, The 6th China-Japan-Korea Foresight Joint Symposium on Gene Delivery and International Symposium on Biomaterials, Sanya, China, 2008
- Forum speaker, 60th anniversary of Dalian Institute of Chemistry and Physics, Chinese Academy of Sciences, Dalian, China, 2009
- Plenary speaker, 4th International Conference in Advanced Drug Delivery, Shanghai, China, 2009
- Honorary Professor, Sichuan University, China, 2009
- Distinguished speaker, Japan Association for The Advancement of Medical Equipment, 2010
- Distinguished speaker, Global Center of Excellence, University of Shizuoka, Japan, 2010
- Distinguished speaker, The Academy of Pharmaceutical Science And Technology, Japan, 2010