Illustration of micelle formation from PEG-b-polycation and DNA. 

We have developed a series of biocompatible and biodegradable polymers that self-assemble with DNA or RNA to form micellar nanoparticles. These nanoparticles consist of a DNA/polyphosphoramidate complex core and a polyethylene glycol (PEG) corona rendering particles more stable in aqueous medium.  These nanoparticles are formed by self assembly, thus have uniform size ranging from tens to a couple hundreds of nanometers. With small and uniform size, good colloidal stability and longer circulation time, these nanoparticles offer opportunity for passive targeting to fenestrated tissues, for example solid tumor and liver sinusoid due to the “enhanced permeability and retention” effect.  The size, morphology and stability can be controlled by adjusting PEG-b-PPA polymer structure.  In addition, cell-specific ligands can be introduced to micelle surface to improve cell binding and targeting.  Our micelle system offers unique advantages on versatile structure, biophysical properties, transfection efficiency and safety.  These favorable characteristics make this micelle system an ideal platform for systematic investigation of delivery mechanism and optimization of tissue-targeted delivery system.  An ability to control nanoparticle stability, DNA or RNA release, cell binding, and intracellular trafficking will be the key to understanding the rate-limiting steps for gene delivery and to optimizing transgene expression efficiency in vivo. We are currently investigating the effect of PEG-b-PPA carrier structure on DNA compaction ability, nanoparticle assembly and stability, transport properties at cell and tissue levels, and delivery efficiency.

Publications

1. Jiang X, Dai H, Ke CY, Mo X, Torbenson MS, Li Z and Mao HQ. PEG-b-PPA/DNA micelles improve transgene expression in rat liver through intrabiliary infusion. Journal of Controlled Release. 122: 297–304 (2007).
2. Sun TM, Du JZ, Yan LF, Mao HQ, Wang J. Self-assembled biodegradable micellar nanoparticles of amphiphilic and cationic block copolymer for siRNA delivery. Biomaterials. 29(32): 4348–4355 (2008).
3. Mao HQ, Leong KW, Design of poly(phosphoester) nanoparticles for nonviral gene therapy. Advances in Genetics. 53: 275-306 (2005).
4. Zhang PC, Wang J, Leong KW, Mao HQ. Ternary complexes comprising polyphosphoramidate gene carriers with different types of charge groups improve transfection efficiency. Biomacromolecules. 6(1): 54-60 (2005).
5. Chen HH, Ho YP, Jiang X, Mao HQ, Wang TH, Leong KW. Quantitative comparison of intracellular unpacking kinetics of polyplexes by a model constructed from quantum dot-FRET. Molecular Therapy. 16(2): 324-332 (2008).