(671h) Posh Inhibitor Peptide Amphiphile Micelles As a Novel Leukemia Therapeutic Modality

Acute lymphoblastic leukemia (ALL) is associated with high-risk and poor prognosis for which few effective treatments exist. Published data has shown that the scaffold peptide â??Plenty of SH3 Domainsâ?? regulates lymphocyte signaling pathways and its disruption by a novel peptide (TAT-POSH) leads to significant cell death in greater than 90% of T cell and B cell leukemias evaluated to date. While TAT has been shown to facilitate moderately enhanced cellular internalization, it carries out its function by macropinocytosis which may not be the best method for cytosolic payload delivery. Peptide amphiphile micelles (PAMs) are biomaterials that have been shown to be internalized by lipid bilayer intercalation which allows for significant cytosolic delivery. By combining POSH peptide with the micellar platform, a novel ALL treatment system capable of broad spectrum anti-neoplastic effects may be achievable.

POSH peptide amphiphiles were synthesized by covalently conjugating two hydrophobic aliphatic palmitic acid tails to POSH peptides which were found to self-assembly into small and mostly spherical micelles in water at very low concentrations. Since ALL is a blood-borne cancer, therapeutics need to be capable of being delivered intravenously so small, spherical micelles are an ideal device. Interestingly, spherical micellization often requires the use of an additional hydrophilic linker (e.g. PEG) to achieve the desirable micelle shape, but the highly hydrophilic and charged nature of the POSH peptide facilitated spherical micelle formation without additional components. Confocal microscopy revealed that fluorescently-labeled POSH PAMs are readily uptaken by even non-phagocytic cells indicating their intracellular payload potential. To determine the enhanced cancer cytotoxicity of POSH PAMs they were incubated with three different leukemic cell lines (murine LM-138, human Mec-1, and human Mec-2) and their effects were compared to the known cytotoxic peptide TAT-POSH. POSH PAMs was found to greatly outperform TAT-POSH inducing enhanced cytotoxicity at every dose and similar cytotoxicity at a sixteenth to an eighth of the dose. The capacity for POSH PAMs to improve cancer cytotoxicity over a gold-standard cell penetrating peptide like TAT is a quite exciting discovery. These results provide strong evidence that POSH PAMs hold tremendous promise as an ALL treatment modality.