An estimated 211000 new cases and 40000 deaths will be attributed breast cancer in the USA in 2006. Novel approaches that allow for a more effective and less toxic chemotherapy for disseminated breast cancer are needed for which the current therapies are largely ineffective. Targeted drug encapsulated nanoparticles may decrease the side effects of available treatment and increase their efficiency resulting in enhanced therapeutic index of available chemotherapies. The targeted delivery of nanoparticles with polypeptides may confer certain advantages when compared to antibodies such as small size, robustness of platform, and synthetic production that can facilitate scale-up production. We report the development of controlled release polymer nanoparticles using a poly (D,L lactic)-poly(ethylene glycol) copolymer with a terminal maleimide functional group (PLA-PEG-MAL). These nanoparticles were conjugated to a polypeptide sequence that has a preferential binding characteristics for the Her-2 receptor, a well characterized antigen that is overexpressed on the surface of breast and pancreatic cancers. The resulting pegylated nanoparticle-peptide bioconjugates were ~120 nm in size and had negative surface charge of ~ -5 mV. The combination of these characteristics is expected to minimize the non-specific clearance of these nanoparticles by the body’s immune system. The conjugation of the peptide does not affect the physical properties of the nanoparticles and we did not observe any nanoparticle aggregation. We next demonstrated a differential cytotoxity of these bioconjugates using docetaxel encapsulated targeted nanoparticles. These bioconjugates specifically bound to and were taken up by the Her2 expressing cells resulting in enhanced differential cytotoxity as compared cells which do not express Her2, and to empty nanoparticle controls. These targeted drug delivery nanoparticles could be used as a powerful therapeutic tool for Her2 expressing cancers.
Keywords: Her2, Poly(lactic acid), PLA, targeted nanoparticles, docetaxel
Topic: Drug Delivery & Therapeutics- Targeting at Molecular, Cellular and Higher Levels.
Figure 1. Targeted nanoparticle-polypeptide conjugates uptake into SKBR-3 cells
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA