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The organometallic ferrocene exhibits amplified anti-tumor activity by targeted delivery via highly selective ligands to αvβ3, αvβ6, or α5β1 integrins
- Publication Year :
- 2021
-
Abstract
- High levels of reactive oxygen species (ROS) in tumors have been shown to exert anti-tumor activity, leading to the concept of ROS induction as therapeutic strategy. The organometallic compound ferrocene (Fc) generates ROS through a reversible one-electron oxidation. Incorporation of Fc into a tumor-targeting, bioactive molecule can enhance its therapeutic activity and enable tumor specific delivery. Therefore, we conjugated Fc to five synthetic, Arg-Gly-Asp (RGD)-based integrin binding ligands to enable targeting of the cell adhesion and signaling receptor integrin subtypes αvβ3, α5β1, or αvβ6, which are overexpressed in various, distinct tumors. We designed and synthesized a library of integrin-ligand-ferrocene (ILF) derivatives and showed that ILF conjugates maintained the high integrin affinity and selectivity of their parent ligands. A thorough biological characterization allowed us to identify the two most promising ligands, an αvβ3 (L2b) and an αvβ6 (L3b) targeting ILF, which displayed selective integrin-dependent cell uptake and pronounced ferrocene-mediated anti-tumor effects in vitro, along with increased ROS production and DNA damage. Hence, ILFs are promising candidates for the selective, tumor-targeted delivery of ferrocene to maximize its anti-cancer efficacy and minimize systemic toxicity, thereby improving the therapeutic window of ferrocene compared to currently used non-selective anti-cancer drugs.
- Subjects :
- Integrins
DNA damage
Metallocenes
Tumor cell cytotoxicity
Cell
Integrin
Biophysics
Bioengineering
Ligand
02 engineering and technology
Ligands
Biomaterials
03 medical and health sciences
Neoplasms
medicine
Humans
Cell adhesion
Receptor
030304 developmental biology
Integrin binding
Metallocene
0303 health sciences
Targeted drug delivery
biology
Chemistry
021001 nanoscience & nanotechnology
α5β1
Integrin alphaVbeta3
In vitro
Cell biology
medicine.anatomical_structure
αvβ6
Mechanics of Materials
Synthetic integrin ligands to αvβ3
Ceramics and Composites
biology.protein
Reactive oxygen specie
Ferrocene
0210 nano-technology
Human
Integrin alpha5beta1
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....2c9751106f01b560e0c36b2a762555bb