Targeted PDT Agent Eradicates TrkC Expressing Tumors
via Photodynamic Therapy (PDT)
- Publication date
- Publisher
Abstract
This
contribution features a small molecule that binds TrkC (tropomyosin
receptor kinase C) receptor that tends to be overexpressed in metastatic
breast cancer cells but not in other breast cancer cells. A sensitizer
for <sup>1</sup>O<sub>2</sub> production conjugated to this structure
gives <b>1</b>-<b>PDT</b> for photodynamic therapy. Isomeric <b>2</b>-<b>PDT</b> does not bind TrkC and was used as a control
throughout; similarly, TrkC– cancer cells were used to calibrate
enhanced killing of TrkC+ cells. Ex vivo, <b>1</b>- and <b>2</b>-<b>PDT</b> where only cytotoxic when illuminated,
and <b>1</b>-<b>PDT</b>, gave higher cell death for TrkC+
breast cancer cells. A 1 h administration-to-illumination delay gave
optimal TrkC+/TrkC–-photocytotoxicity, and distribution studies
showed the same delay was appropriate in vivo. In Balb/c mice, a maximum
tolerated dose of 20 mg/kg was determined for <b>1</b>-<b>PDT</b>. <b>1</b>- and <b>2</b>-<b>PDT</b> (single,
2 or 10 mg/kg doses and one illumination, throughout) had similar
effects on implanted TrkC– tumors, and like those of <b>2</b>-<b>PDT</b> on TrkC+ tumors. In contrast, <b>1</b>-<b>PDT</b> caused dramatic TrkC+ tumor volume reduction (96%
from initial) relative to the TrkC– tumors or <b>2</b>-<b>PDT</b> in TrkC+ models. Moreover, 71% of the mice treated
with 10 mg/kg 1-PDT (<i>n</i> = 7) showed full tumor remission
and survived until 90 days with no metastasis to key organs