报告题目：Tumor Microenvironment and Drug Delivery
报告时间：2015年4月10日（周五）9：30-12：00
报告地点：图书馆五楼第一学术报告厅
报 告 人：Leaf Huang教授
（美国北卡大学教堂山分校教授）
主 持 人：何仲贵教授
（沈阳药科大学药剂学科主席）
主办单位：药剂学学科
沈阳药科大学研究生处（学科建设办公室）
辽宁省研究生现代药物领域创新与交流中心
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报告人简介
黄力夫教授Leaf Huang, Ph.D. is the Fred Eshelman Distinguished Professor, Division of Molecular Pharmaceutics in the Eshelman School of Pharmacy, University of North Carolina at Chapel Hill. Dr. Huang’s research has been in the area of gene therapy and targeted drug delivery. He has pioneered the liposome non-viral vector and has designed and manufactured the cationic lipid vector for the first non-viral clinical trial in 1992. His current work centers on nanoparticle vectors for gene transfer in tumor and 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. He has authored or co-authored more than 350 peer-reviewed papers and more than 140 reviews and book chapters with an H-index of 102. He is also the inventor or co-inventor of 17 US and foreign patents. In 2004, he received the Alec D. Bangham MD FRS Achievement Award, which is the highest honor in liposome research. He was the recipient of the 2013 Distinguished Pharmaceutical Scientist Award which is the highest scientific recognition of the American Association of Pharmaceutical Scientists. Dr. Huang has also co-founded 5 biotech start-ups in the past.
报告内容简介
Targeting siRNA to Tumor Cells
We have developed self-assembled nanoparticles covalently coupled with an anisamide ligand that binds to the surface sigma receptor that is overexpressed in human tumor cells. The target-specific LPH 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, a large amount of the injected siRNA accumulated in the tumor; this accumulation resulted in nearly complete silencing of the target oncogenes throughout the entire tumor.
We have also delivered therapeutic siRNA to melanoma cells as solid tumor or lung metastasis and showed significant reduction in the tumor load in the treated animals.
Nanoparticles with Enhanced Cargo Escape from the Endosome
To enhance de-assembly of nanoparticle in acidic endosomes, the core of the nanoparticle has been replaced with calcium phosphate nanoprecipitates. The resulting nanoparticles, referred to as LCP, are about forty-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.
Remodeling Tumor Microenvironment with Nanomedicines
Mature tumor contains extensive stroma structure that is made of primarily collagen and hyaluronic acid. Tumor associated fibroblasts, or TAFs, are recruited by tumor cells to build the stroma that separates tumor vessels and tumor cells.
We have discovered that combined nanoparticles containing gemcitabine and cisplatin efficiently kill TAFs and down-regulate stroma, resulting in excellent inhibition of tumor growth.
A Novel Cancer Vaccine That Can Be Enhanced by Down-Regulating the Suppressive Tumor Microenvironment
Using the LCP nanoparticles, we have developed a novel cancer vaccine by encapsulating a peptide of a tumor-associated antigen or its mRNA. Subcutaneous administration of the vaccine nanoparticles delivers the antigen to the dendritic cells in the draining lymph nodes and stimulates a strong cytotoxic T-lymphocyte response leading to inhibition of tumor growth.
Vaccine activity can be further enhanced by delivering siRNA against key cytokines, such as TGF-β, that control the suppressive tumor microenvironment. We are currently investigating siRNA, miRNA and/or small-molecule drugs that can inhibit the myelo-derived suppressive cells and Treg cells to further enhance the vaccine activity
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