Peptide-Conjugated Micelles Make Effective Mimics of the TRAIL Protein for Driving Apoptosis in Colon Cancer.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) drives apoptosis selectively in cancer cells by clustering death receptors (DR4 and DR5). While it has excellent in vitro selectivity and toxicity, the TRAIL protein has a very low circulation half-life in vivo, which has hampered clinical development. Here, we developed core-cross-linked micelles that present multiple copies of a TRAIL-mimicking peptide at its surface. These micelles successfully induce apoptosis in a colon cancer cell line (COLO205) via DR4/5 clustering. Micelles with a peptide density of 15% (roughly 1 peptide/45 nm2) displayed the strongest activity with an IC50 value of 0.8 µM (relative to peptide), demonstrating that the precise spatial arrangement of ligands imparted by a protein such as a TRAIL may not be necessary for DR4/5/signaling and that a statistical network of monomeric ligands may suffice. As micelles have long circulation half-lives, we propose that this could provide a potential alternative drug to TRAIL and stimulate the use of micelles in other membrane receptor clustering networks.

Polymer mediated transport of the Hsp90 inhibitor LB76, a polar cyclic peptide, produces an Hsp90 cellular phenotype.

LB76 is a cyclic peptide that shows great promise as a selective heat shock protein 90 (Hsp90) inhibitor. However despite strong binding to and inhibition of Hsp90 in cell lysate its polar structure prevents it from crossing the cell membrane. We have developed a pH responsive polymer nanoparticle that effectively encapsulates LB76 from solution without need for purification. The nanoparticle releases the molecule upon crossing the cell membrane. Treatment of human colon cancer HCT116 cells with nanoparticles laden with LB76 produces the typical phenotype associated with Hsp90 inhibition, providing evidence of a therapeutically active payload.