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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., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Abstract New unsymmetrical pentamethine cyanine dyes containing two non-equivalent reactive groups selected from carboxyl, amino and hydroxyl in different combinations were synthesized and their spectral properties investigated. Amino and hydroxy groups were used for binding the dyes to the anticancer drug, chlorambucil (CLB) via biodegradable amide or ester linker while the second reactive functionality could be utilized for attachment at mild conditions to a targeting carrier such as an antibody or peptide. These conjugates can thereby potentially be suitable for fluorescence-based monitoring of drug delivery. The CLB release profiles triggered by biodegradable linker were investigated in buffer solutions and cell medium using LC-MS and spectrofluorimetric methods. Graphical abstract Image 1 Highlights • New unsymmetrical, bifunctional pentamethine cyanine dyes were synthesized. • These dyes contain carboxyl, amino and hydroxyl groups in different combinations. • Amino and hydroxy groups were bound to anticancer drug, chlorambucil (CLB). • Spectral properties and CLB release profiles of the conjugates were investigated. • These conjugates are suitable for fluorescence-based monitoring of drug delivery. [ABSTRACT FROM AUTHOR]