Nintedanib-αVβ6 Integrin Ligand Conjugates Reduce TGFβ-Induced EMT in Human Non-Small Cell Lung Cancer

Abstract

Growth factors and cytokines released in the lung cancer microenvironment promote an epithelial-to-mesenchymal transition (EMT) that sustains the progression of neoplastic diseases. TGFβ is one of the most powerful inducers of this transition, as it induces overexpression of the fibronectin receptor, αvβ6 integrin, in cancer cells which, in turn, is strongly associated with EMT. Thus, αvβ6 integrin receptors may be exploited as a target for the selective delivery of anti-tumor agents. We introduce three novel synthesized conjugates, in which a selective αvβ6 receptor ligand is linked to nintedanib, a potent kinase inhibitor used to treat advanced adenocarcinoma lung cancer in clinics. The αvβ6 integrin ligand directs nintedanib activity to the target cells of the tumor microenvironment, avoiding the onset of negative side effects in normal cells. We found that the three conjugates inhibit the adhesion of cancer cells to fibronectin in a concentration-dependent manner and that αvβ6-expressing cells internalized the conjugated compounds, thus permitting nintedanib to inhibit 2D and 3D cancer cell growth and suppress the clonogenic ability of the EMT phenotype as well as intervening in other aspects associated with the EMT transition. These results highlight αvβ6 receptors as privileged access points for dual-targeting molecular conjugates engaged in an efficient and precise strategy against non-small cell lung cancer.

Advances in active targeting of ligand-directed polymeric nanomicelles via exploiting overexpressed cellular receptors for precise nanomedicine

“…The RGD peptide (Arg-Gly-Asp) is commonly known to target integrin. 41 In this regard, Lei et al successfully fabricated a new dual-targeted nanomicelles decorated with Ang-2 (Angiopep-2) and cRGD peptide to exploit numerous receptors massively expressed on the exterior of glioma cells. 42 The outer shell of the nanomicelles was constructed from two types of hydrophilic copolymers; [PEG] and β-cyclodextrin (β-CD) attached together via condensation reaction, followed by decoration with Ang-2 and cRGD via click reaction for targeting LRP-1 (low-density lipoprotein receptor-related protein-1) and α v β 3 integrin receptors, respectively to form Ang-2-PEG-β-CD and cRGD-PEG-β-CD.…”