Abstract

For cancer diagnosis and therapy, we are developing activatable cell penetrating peptides (ACPPs), synthetic molecules with a novel amplifying mechanism for homing to diseased tissues. ACP Ps are polycationic cell penetrating peptides whose cellular uptake is minimized by a polyanionic inhibitory domain and restored if the peptide linker connecting the two domains is cleaved. Local activity of specific proteases cuts the linker and causes amplified adhesion and uptake in tumors. ACP Ps sensitive to matrix metalloproteinases 2 and -9 enable magnetic resonance imaging (MRI), fluorescence-guided surgery, delivery of chemotherapy, and radiosensitization. We have also developed fluorescent peptides that light up peripheral nerves to show surgeons where not to cut.

We are testing the hypothesis that life-long memories are stored as the pattern of holes in the perineuronal net (PNN), a specialized form of extracellular matrix deposited around neurons during critical periods of brain development. The PNN contains long-lived molecules, can be modified enzymatically and is interrupted by holes where synapses occur. We postulate that new memories are recorded by carving new holes to form novel synapses or by expanding existing holes to strengthen old synapses. Experimental tests are underway.

Crisp, J.L., et al. 2014. Dual targeting of integrin αvβ3 and matrix metalloproteinase-2 for optical imaging of tumors and chemotherapeutic delivery. Mol. Cancer Ther. 13: 1514-25. Tsien, R.Y. 2013. Very long-term memories may be stored in the pattern of holes in the perineuronal net. Proc. Natl. Acad. Sci. USA . 110: 12456-61.