Improvement of meta-tetra(hydroxyphenyl)chlorin-like photosensitizer selectivity with folate-based targeted delivery.: Synthesis and in vivo delivery studies

The cell membrane folate receptor (FR) is a molecular target for tumor-selective drug delivery, including delivery of photosensitizers for anticancer photodynamic therapy (PDT). Tumor selectivity of metatetra(hydroxyphenyl)chlorin (m-THPC), a photosensitizer used in PDT clinical trials, demonstrates a low tumor-to-normal epithelial uptake ratio. We report on the synthesis and on the photophysical properties of a m-THPC-like photosensitizer I conjugated to folic acid (compound 8). A comparative study of the accumulation of photosensitizers I and 8 is described. Nude mice were xenografted with FR-alpha-positive KB or HT-29 cells lacking FR-alpha as a negative control. Using optical fiber fluorimetry, we demonstrated that conjugate 8 exhibited enhanced accumulation in KB tumors compared to 14 h after injection. No significant difference between KB and HT-29 tumors was observed in case of compound 1. Tumor-to-normal tissue ratio exhibited a very interesting selectivity for conjugate 8 (5: 1) in KB tumors 4 h postinjection.