Targeted Delivery and Site-Specific Activation of β‑Cyclodextrin-Conjugated Photosensitizers for Photodynamic Therapy through a Supramolecular Bio-orthogonal Approach

Targeted delivery of photosensitizers
using hydrophilic and tumor-directing
carriers and site-specific activation of their photocytotoxicity are
two common strategies to enhance the specificity of anticancer photodynamic
therapy. We report herein a novel supramolecular bio-orthogonal approach
to integrate these two functions. A β-cyclodextrin-substituted
aza-boron-dipyrromethene-based photosensitizer was first complexed
with a ferrocene-substituted black-hole quencher to inhibit its photosensitizing
ability. Upon encountering the adamantane moieties that had been delivered
to target cancer cells through specific binding of the conjugated
peptide to the overexpressed epidermal growth factor receptor, the
ferrocene-based guest species were displaced due to the stronger binding
interactions between β-cyclodextrin and adamantane, thereby
restoring the photodynamic activity of the photosensitizer. Hence,
this two-step process enabled targeted delivery and site-specific
activation of the photosensitizer, as demonstrated through a series
of experiments in aqueous media, in a range of cancer cell lines and
in tumor-bearing nude mice.