Multifunctional human serum albumin-therapeutic nucleotide conjugate with redox and pH-sensitive drug release mechanism for cancer theranostics

• Published in: Bioorganic & medicinal chemistry letters Vol. 27; no. 16; pp. 3925 - 3930
• Main Authors: Lisitskiy, Vladimir A., Khan, Hamda, Popova, Tatyana V., Chubarov, Alexey S., Zakharova, Olga D., Akulov, Andrey E., Shevelev, Oleg B., Zavjalov, Evgenii L., Koptyug, Igor V., Moshkin, Mikhail P., Silnikov, Vladimir N., Ahmad, Saheem, Godovikova, Tatyana S.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.08.2017
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Dual-responsive drug release; Humans; Hydrogen-Ion Concentration; Modified human serum albumin; Molecular Structure; Multimodal molecular imaging; Nucleotides - chemistry; Oxidation-Reduction; Serum Albumin - chemistry; Structure-Activity Relationship; Theranostic prodrug; Thymine Nucleotides - chemistry; Thymine Nucleotides - pharmacology; Trifluorothymidine conjugate; Modified human serum albumin; NTJKQVMEBUIIMX-UHFFFAOYSA-N; SAPZVRNVBKOGQV-UHFFFAOYSA-N; Trifluorothymidine conjugate; Dual-responsive drug release; Multimodal molecular imaging; Theranostic prodrug; ZJJFDKYTHKJYKA-PBTLETOKSA-M
• ISSN: 0960-894X; 1464-3405; 1464-3405
• DOI: 10.1016/j.bmcl.2017.05.084

[Display omitted] We report on the synthesis and properties of a new multimodal theranostic conjugate based on an anticancer fluorinated nucleotide conjugated with a dual-labeled albumin. A fluorine-labeled homocysteine thiolactone has been used as functional handle to synthesize the fluorinated albumin and couple it with a chemotherapeutic agent 5-trifluoromethyl-2′-deoxyuridine 5′-monophosphate (pTFT). The conjugate allows for direct optical and 19F magnetic resonance cancer imaging and release of the drug upon addition of glutathione. Interestingly, the pTFT release from albumin conjugate could only be promoted by the increased acidity (pH 5.4). The in vitro study and primary in vivo investigations showed stronger antitumor activity than free pTFT.