Abstract
Drug conjugates consisting of an antineoplastic drug and a targeting receptor ligand could be effective to overcome the heavy side effects of unselective anticancer agents. To address this need, we report here the results of a project aimed to study agonist and antagonist integrin ligands as targeting head of molecular cargoes for the selective delivery of 5-fluorouracil (5-FU) to cancer or noncancer cells. Initially, two fluorescent β-lactam-based integrin ligands were synthesized and tested for an effective and selective internalization mediated by α4β1 or α5β1 integrins in Jurkat and K562 cells, respectively. No cellular uptake was observed for both fluorescent compounds in HEK293 noncancerous control cells. Afterward, three conjugates composed of the β-lactam-based integrin ligand, suitable linkers, and 5-FU were realized. The best compound E, acting as α5β1 integrin agonist, is able to selectively deliver 5-FU into tumor cells, successfully leading to cancer cell death.
Highlights
Drug conjugates consisting of an antineoplastic drug and a targeting receptor ligand could be effective to overcome the heavy side effects of unselective anticancer agents
Integrins are overexpressed in many types of cancer cells, and they have been implicated in mediating several hallmarks of cancer, including cancer cell proliferation, dormancy, survival, stemness, metabolic adaptation, and metastatic niche.[4−7] In particular, α5β1 integrin plays a predominant role in tumor-induced angiogenesis, migration, and invasion of cancer cells; it is aberrantly upregulated in various types of cancers; and its overexpression is correlated with poor prognosis.[8,9]
The substitution of the 4-acetoxy group occurred with a complete control of the stereoselectivity obtaining exclusively the trans diastereoisomer 1.38 Compound 1 was acylated on the β-lactam nitrogen atom with the commercially available o-tolylisocyanate to give 2, in order to get the specific o-tolylureidic residue necessary for modulating the affinity toward the integrin receptor
Summary
Drug conjugates consisting of an antineoplastic drug and a targeting receptor ligand could be effective to overcome the heavy side effects of unselective anticancer agents. Targeted drug delivery can be an effective strategy to increase the bioavailability of therapeutics, to cancer tissue, to decrease the heavy side effects (nonspecific delivery to healthy tissue), and to improve clinical outcomes.[1] It has been recognized how molecular interactions between receptors and ligands that control cellto-cell communications may represent an effective target.[2]. Considerable progresses in tumor-targeting strategies have been achieved with antineoplastic drug conjugates as delivery systems that consist of a tumor-targeting group and an antineoplastic drug, connected by a linker In this context, integrins are peculiar receptors because they activate intracellular signaling pathways to regulate cell growth, survival, migration, invasion, and angiogenesis.[3]. Despite its important role in inflammation and immunity, α4β1 integrin is expressed on several types of tumor cells and contributes to migration and metastasis, tumor angiogenesis, and development of drug resistance.[6,9,13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
