Double-Targeting Using a TrkC Ligand Conjugated to Dipyrrometheneboron Difluoride (BODIPY) Based Photodynamic Therapy (PDT) Agent

Abstract

A molecule <b>1</b> (IY-IY-PDT) was designed to contain a fragment (IY-IY) that targets the TrkC receptor and a photosensitizer that acts as an agent for photodynamic therapy (PDT). Molecule <b>1</b> had submicromolar photocytotoxicities to cells that were engineered to stably express TrkC (NIH3T3-TrkC) or that naturally express high levels of TrkC (SY5Y neuroblastoma lines). Control experiments showed that <b>1</b> is not cytotoxic in the dark and has significantly less photocytotoxicity toward cells that do not express TrkC (NIH3T3-WT). Other controls featuring a similar agent <b>2</b> (YI-YI-PDT), which is identical and isomeric with <b>1</b> except that the targeting region is scrambled (a YI-YI motif, see text), showed that <b>1</b> is considerably more photocytotoxic than <b>2</b> on TrkC⁺ cells. Imaging live TrkC⁺ cells after treatment with a fluorescent agent <b>1</b> (IY-IY-PDT) proved that <b>1</b> permeates into TrkC⁺ cells and is localized in the lysosomes. This observation indirectly indicates that agent <b>1</b> enters the cells via the TrkC receptor. Consistent with this, the dose-dependent PDT effects of <b>1</b> can be competitively reduced by the natural TrkC ligand, neurotrophin NT3