Combining Gene and Chemo Therapy using Multifunctional Polymeric Micelles

Non-viral gene carriers composed of biodegradable polymers or lipids have been considered as a safer alternative for gene carriers over viral vectors. We have developed multi-functional nano-micelles for both drug and gene delivery application. Polyethyleneimine (PEI) was modified by grafting stearic acid (SA) and formulated to polymeric micelles (PEI-SA) with positive surface charge for gene and drug delivery. Our results showed that PEI-SA micelles provided high siRNA binding efficiency. In addition, siRNA delivered by PEI-SA carriers also demonstrated significantly high cellular uptake even in the presence of serum proteins. The post-transcriptional gene silencing efficiency was greatly improved by the polyplex formulated by 10k PEI-SA/siRNA. The amphiphilic structure of PEI-SA micelles provided advantages for multifunctional tasks; where the hydrophilic shell modified with cationic charges can electrostatically interact with DNA or siRNA, and the hydrophobic core can serve as payloads for hydrophobic drugs, making it a promising multifunctional vehicle for both genetic and chemotherapy application.




References:
[1] K.A. Whitehead, R. Langer, D.G. Anderson, "Knocking down barriers:
advances in siRNA delivery", Nat. Rev. Drug Discov., vol.8 no. 2,
pp.129-138, Feb.2009.
[2] H.S. Kwon, H.C. Shin, J.S. Kim, "Suppression of vascular endothelial
growth factor expression at the transcriptional and post-transcriptional
levels", Nucleic Acids Res, vol. 33, no.8, e74, April 2005.
[3] P.Y. Lu, F.Y. Xie, M.C. Woodle, "Modulation of angiogenesis with siRNA
inhibitors for novel therapeutics", Trends in Mol.Med., vol. 11, no.3,
pp.104-113, March 2005.
[4] F. Alexis, E. Pridgen, L.K. Molnar, O.C. Farokhzad, "Factors affecting the
clearance and biodistribution of polymeric nanoparticles", Mol.Pharm. vol.
5, no. 4, pp.505-515, Aug. 2008.
[5] W.T. Kuo, H.Y. Huang, Y.Y. Huang, "Polymeric micelles comprising
stearic acid-grafted polyethyleneimine as nonviral gene carrier", J. of
Nanosci. and Nanotech., to be published.
[6] H. Maeda, K. Greish, J. Fang, "The EPR effect and polymeric drugs: A
paradigm shift for cancer chemotherapy in the 21st century", Adv. In Poly.
Sci., vol. 193, pp. 103-121, Nov. 2006.