ABSTRACT
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≈710â 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.
Subject(s)
Carbocyanines/chemistry , Chlorambucil/chemistry , Drug Carriers/chemistry , Fluorenes/chemistry , Octreotide/metabolism , Resins, Synthetic/chemistry , Xanthenes/chemistry , Aminobutyrates/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , CHO Cells , Carbocyanines/metabolism , Cell Line, Tumor , Cell Survival/drug effects , Chlorambucil/pharmacology , Cricetulus , Drug Carriers/metabolism , Fluorescent Dyes/chemistry , Fluorescent Dyes/metabolism , Gene Expression Regulation, Neoplastic , Humans , Molecular Targeted Therapy/methods , Receptors, Somatostatin/chemistry , Receptors, Somatostatin/genetics , Xanthenes/metabolismABSTRACT
Conjugation of an anticancer drug with a cancer-specific carrier and a fluorescent dye to form a theranostic system enables real time monitoring of targeted drug delivery (TDD). However, the fluorescence signal from the dye is affected by the light absorption and scattering in the body, photobleaching, and instrumental parameters. Ratiometric measurements utilizing two fluorescence signals of different wavelengths are known to improve sensitivity, reliability and quantitation of fluorescence measurements in biological media. Herein, a novel theranostic system comprising the anticancer drug chlorambucil (CLB), cancer-specific peptide octreotide amide (OctA), and a long-wavelength dual fluorescent cyanine dye IRD enabling ratiometric monitoring of drug delivery was developed and evaluated on the cancer cell line PANC-1.
ABSTRACT
Compact carriers for peptidyl delivery systems (PDSs) loaded with various drugs were synthesized using a simple and convenient solid phase organic synthesis strategy, including semi-orthogonal functional group protection schemes. Each attachment point of the compact carrier can thus be bound to an anticancer agent through a biodegradable covalent link. Chemo- and biostability experiments of a model peptidyl platform loaded with three different drugs revealed pH and liver homogenate (metabolic) dependent sequential release behavior. The versatility of this approach will serve to expedite the preparation of PDS libraries. This approach may prove useful for applications suitable for personalized medicine where multiple drug delivery is required in a sequential and controlled fashion.
Subject(s)
Drug Delivery Systems , Peptides/administration & dosage , Cell Line , Chromatography, High Pressure Liquid , Humans , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Electrospray IonizationABSTRACT
Bi-nuclear amino acid platforms loaded with various drugs for conjugation to a peptide carrier were synthesized using simple and convenient orthogonally protective solid-phase organic synthesis (SPOS). Each arm of the platform carries a different anticancer agent linked through the same or different functional group, providing discrete chemo- and bio-release profiles for each drug, and also enabling "switch off/switch on" regulation of drug cytotoxicity by conjugation to the platform and to a cell targeting peptide. The versatility of this approach enables efficient production of drug-loaded platforms and determination of favorable drug combinations/modes of linkage for subsequent conjugation to a carrier moiety for targeted cancer cell therapy. The results presented here potentiate the application of amino acid platforms for targeted drug delivery (TDD).
