Double-targeting using a TrkC ligand conjugated to dipyrrometheneboron difluoride (BODIPY) based photodynamic therapy (PDT) agent.
A molecule 1 (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 1 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 1 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 2 (YI-YI-PDT), which is identical and isomeric with 1 except that the targeting region is scrambled (a YI-YI motif, see text), showed that 1 is considerably more photocytotoxic than 2 on TrkC(+) cells. Imaging live TrkC(+) cells after treatment with a fluorescent agent 1 (IY-IY-PDT) proved that 1 permeates into TrkC(+) cells and is localized in the lysosomes. This observation indirectly indicates that agent 1 enters the cells via the TrkC receptor. Consistent with this, the dose-dependent PDT effects of 1 can be competitively reduced by the natural TrkC ligand, neurotrophin NT3.
Department of Chemistry, Texas A & M University , Box 30012, College Station, Texas 77842, United States.
Anyanee
A
Kamkaew
Kevin
K
Burgess
D000818:Animals; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D008024:Ligands; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020812:Receptor, trkC / Q000378:metabolism*
C095489:4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; D001896:Boron Compounds; D008024:Ligands; D017319:Photosensitizing Agents; D020812:Receptor, trkC