Grant: Discovery Grants Program - Individual

Among polymers, dendrimers are unique synthetic macromolecules of nanometer dimensions with highly branched structure and globular shape capable of transporting DNA, RNA and drug with high efficiency. This research proposal is designed to study the structural organization of dendrimer complexes with DNA and RNA, using laser induced fluorescence capillary electrophoresis, FTIR, CD spectroscopic methods and atomic force microscopy (AFM). In recent reports from our laboratory, we have analysed the structural organizations of cationic lipid complexes with DNA and RNA and examined their potential applications in gene delivery (1, 2). In a constant search for designing tools to deliver gene in vivo, a variety of synthetic polymers have been tested and used. The most common polyamidoamide dendrimers (PAMAM)) are positively charged at physiological pH and strongly react with DNA and RNA. We will analyse the complexation of dendrimers with different compositions such as polyamidoamine (PAMAM) generations G2 to G6, methoxypoly(ethylene glycol) polyamidoamine (mPEG-PAMAM-G3) and mPEG-PAMAM-G4) with DNA and RNA (miRNA, siRNA and tRNA) in vitro at physiological conditions. Laser induced fluorescence capillary electrophoresis, FTIR and CD spectroscopic methods, as well as atomic force microscopy (AFM) will be used to analyse the nature of dendrimer interaction with DNA and RNA. The stability, structural flexibilities, biopolymer condensation and particle formation of the dendrimer-nucleic acid complexes will be determined. Furthermore, the molecular modeling based on molecular dynamic simulations will be used for the dendrimer complexes with DNA and RNA, in order to locate the accurate position of dendrimer, in the major and minor grooves of DNA or RNA duplex. The application of dendrimers in gene delivery will be evaluated. This will be compared with other delivery systems, such as cationic lipids and poly(ethylene glycol). The advantages and disadvantages of each delivery tool will be explored in this research proposal.