Facile Synthesis of Cyclic Peptide–Phthalocyanine Conjugates for Epidermal Growth Factor Receptor-Targeted Photodynamic Therapy

A facile procedure for in situ peptide
cyclization and phthalocyanine
conjugation was developed by utilizing a bifunctional linker incorporated
with a bis­(bromomethyl)­benzene unit and a cyclopentadiene moiety.
These functional groups facilitated the nucleophilic substitution
with the two cysteine residues of the linear peptides followed by
the Diels–Alder reaction with the maleimide moiety attached
to a zinc­(II) phthalocyanine. With this approach, three cyclic peptide–phthalocyanine
conjugates were prepared in 20–26% isolated yield via a one-pot
procedure. One of the conjugates containing a cyclic form of the epidermal
growth factor receptor (EGFR)-binding peptide sequence CMYIEALDKYAC
displayed superior features as an advanced photosensitizer. It showed
preferential uptake by two EGFR-positive cancer cell lines (HT29 and
HCT116) compared with two EGFR-negative counterparts (HeLa and HEK293),
resulting in significantly higher photocytotoxicity. Intravenous administration
of this conjugate into HT29 tumor-bearing nude mice resulted in selective
localization in tumor and effective inhibition of tumor growth upon
photodynamic treatment.