Multivalent interactions play a critical role in cellular biochemistry. We have developed a novel approach to control the arrangement of cell-targeting ligand on nanoparticle surfaces using linear-dendritic copolymeric (LDP) system that self-assembles into micelles, the surface of which bears specific number of ligands in a clustered pattern. Previously our group has reported the synthesis and biological assessment of such �Patchy� micelles for the first time, where the targeting ligand folic acid was clustered on the miceller surface [1]. It was found that both cellular uptake and tumor accumulation of these micelles critically depends on the number of targeting peptides per cluster.In this project we have immoblized a cancer cell targeting peptide, Lyp-1 (CGNKRTRGC) [2] on a linear-dendritic copolymer through Cu-mediated azide-alkyne click chemistry. As a linear block, poly(�-benzyl aspartate) was utilized which was attached to a generation 4 polyester dendron. The stoichiometric mixing of Lyp-1 functionalized and unfunctionalized LDP molecule results in micelles with a definite number of Lyp-1 arranged over the miceller surface in a clustered pattern. The micelles were within the size range of 80-90 nm with a CMC in the order of 10-5M. The Lyp-1 peptide bearing micelles showed higher uptake in MDA-MB-435 cell line compared to the unfunctionalized micelles, indicating ligand-mediated uptake. It was found that though the average number of ligands per micelles is the same, cellular uptake in MDA-MB-435 cells was dependent on the number of Lyp-1 per cluster, indicating the spatial affect of molecular crowding on ligand-receptor engagement.References 1) Poon Z, Chen, S., Engler, A. C., Lee, H., Alas, E, Maltzahn, G-v., Bhatia, S. N., Hammond, P.T., Angew. Chem. Int. Ed. 2010  , 49, 7266 (2) Laakkonen, P.; Porkka, K.; Hoffman, J.A.; Ruoslahti, E., Nat. Med. 2002  , 8, 751

Linear-dendritic copolymer micelles for multivalent targeting

245th National Meeting (2013)

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