Nanotech 2010

Targeting tumor associated macrophages using clodronate-loaded PLGA nanoparticles

G. Sharma, P. Karmali, M. Ramirez, Hui Xie, E. Ruoslahti, J. Smith
Burnham Institute for Medical Research, US

Keywords: tumor associated macrophages, clodronatge, PLGA nanoparticles, LyP-1 peptide

Abstract:

There is increasing evidence now that tumor associated macrophages (TAMs) play a key role in tumor growth and metastasis by promoting tumor angiogenesis. Macrophages are also prominent in tumor tissues, comprising up to 80% of the cell mass in breast carcinoma. Although therapeutic targeting of TAMs is still in its infancy, the above reasons highlight the importance of TAMs as a validated therapeutic target for nanoparticle-mediated cancer therapy. We propose a novel therapy for cancer by targeting TAMs using clodronate-loaded LyP-1-functionalized PLGA nanoparticles. Clodronate is a promising drug for TAM-mediated tumor therapy. Once delivered inside the cell cytoplasm, it reacts with nonhydrolyzable analogue of ATP resulting in apoptosis. Towards this end we first developed amine-modified, PEGylated PLGA nanoparticles (NPs) encapsulating clodronate as an anti-macrophage drug and showed that it can selectively deplete macrophages while showing little or no toxicity to non-phagocytic cells. We then functionalized these particles with a tumor targeting element and showed that they preferentially accumulate in tumors. Tumor therapy experiments are currently underway to investigate the effect of these NPs on TAM abrogation and tumor suppression.
 
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