Dr. Ron Shmueli

dr shumeli with lens flare copy

 

 

 

 

 

 

 

 

 

 

THERAPEUTIC NANO- AND MICROPARTICLES FOR ANGIOGENESIS DEPENDENT DISEASES

There are a number of diseases that are caused by, or depend on, irregular angiogenesis. In cancer, tumors require new vasculature in order to proliferate. In neovascular age-related macular degeneration (NVAMD), aberrant angiogenesis can result in leakage that damages the retina, causing progressive blindness in patients. Other ocular diseases, such as macular edema and proliferative diabetic retinopathy, also depend on diseased blood vessels, impairing the sight of many millions of people around the world. Therefore, blocking these pathologies has been, and continues to be, an important target of research and therapy. Peptide delivery and genetic therapy are two promising strategies for the treatment of a number of diseases. Gene therapy can be used to replace lost function both in the case of inherited and acquired diseases, such as in cancer. Here, a non-viral polymeric strategy is described for the delivery of DNA. Poly(beta-amino esters) (PBAE) are a class of cationic, hydrolytically degradable polymers that can electrostatically complex with genetic material to form gene delivery nanoparticles. The modular structure of the PBAEs allows for the creation of a library of structures with varying transfection abilities. These PBAEs are used to deliver both reporter and functional genes. Polymer structures that optimally transfect cancer cell types, such as small cell lung cancer, and endothelial cell types, such as human retinal endothelial cells, are identified. The delivery of a functional gene in vivo shows inhibition of tumor growth in a mouse model. The delivery of reporter genes allows for the identification of PBAEs that can preferentially transfect retinal endothelial cells over retinal epithelial cells in vitro. Therefore, it is shown that PBAEs can be a useful platform to deliver DNA both directly to cancer cells and to endothelial cells as a treatment for angiogenesis dependent diseases.

Peptides have a number of favorable therapeutic properties, such as high specificity. Certain serpin-derived and collagen-IV derived peptides have been shown to have potent in vitro and in vivo anti-angiogenic properties. However, peptides are often difficult to translate to the clinic due to high biological clearance and poor biodistribution. Here, the use of nanoparticle and microparticle formulations are described that can counter these limitations and extend the activity of anti-angiogenic peptides by controlled release over time. A number of poly(lactide-co-glycolide) (PLGA) based nanoparticle systems are also developed for the release and passive targeting of the collagen-IV derived peptide for cancer applications. A composite polymeric microparticle system, using PBAE and PLGA, is developed for the treatment of NVAMD. This delivery system is able to release the serpin-derived peptide and inhibit neovascularization in a clinically relevant mouse model over many months. A PLGA microparticle system is also optimized for the release of the collagen-IV derived peptides, with improved long-term efficacy observed in the clinically relevant mouse model.

March, 2015