Peptide‐Driven Targeted Drug‐Delivery System Comprising Turn‐On Near‐Infrared Fluorescent Xanthene–Cyanine Reporter for Real‐Time Monitoring of Drug Release

Targeted drug delivery (TDD) is an efficient strategy for cancer treatment. However, the real-time monitoring of drug delivery is still challenging because of a pronounced lack of TDD systems capable of providing a near-infrared (NIR) fluorescence signal for the detection of drug-release events. Herein, a new TDD system, comprising a turn-on NIR fluorescent reporter attached to an anticancer drug and targeting peptide, is reported. This system provides both TDD and NIR fluorescence monitoring of drug-release events in target tissue. In this TDD system, a new carboxy-derivatized xanthene-cyanine (XCy) dye is attached to an anticancer drug, chlorambucil (CLB), through a hydrolytically cleavable ester linker and coupled to a targeting peptide, octreotide amide (OCTA), which is specific to somatostatin receptors SSTR-2 and STTR-5 overexpressed on many tumor cells. This OCTA-G-XCy-CLB (G: γ-aminobutyric acid) conjugate exhibits no detectable fluorescence, whereas, upon the hydrolytic cleavage of the ester linker, a bright NIR fluorescence appears at λ≈710 nm; this signals release of the drug. Real-time TDD monitoring is demonstrated for the example of the human pancreatic cancer cell line overexpressing SSTR-2 and STTR-5, in comparison with the noncancerous Chinese hamster ovary cell line, which contains a reduced number of these receptors.