The first integrins β3-mediated cellular and nuclear targeting therapeutics for prostate cancer.

Prostate cancer is one of the most commonly diagnosed cancers in men, leading to a high mortality rate due to a lack of effective anticancer treatment. Current anticancer chemotherapeutics are often administrated at suboptimal doses because of nonspecific toxicities to normal tissues, resulting in the eventual failure of therapy as well as the development of drug resistance and metastatic disease. Therefore, ligand-targeted therapeutics have the great potential of improving the selective anticancer toxicity. Integrins β3 (αvβ3 and αIIbβ3) are an important cell adhesion molecular family, overexpressed on both cell membrane and perinuclear region of prostate cancer cells, and play a key role in the progression and metastasis of prostate cancer, making them an attractive target for anticancer therapy. However, their clinical impacts have been limited due to lack of specific ligands. Here, for the first time, we have identified a peptide Arginine-Tryptophan-(D-Arginine)-Asparagine-Arginine as an integrins β3 specific ligand, named B3int, which shows superior selectivity to integrins β3 over other integrin subunits. B3int has high affinity to integrins β3 with a Kd value of 0.2 nM, which is 7-fold higher than c-RGDyK (1.4 nM), a well-established integrin αvβ3 ligand. In addition, B3int shows high specificity for integrins β3, and can selectively target integrin β3 overexpressed cancer cells in vitro and in vivo. Most importantly, B3int-modified liposomes (B3int-LS-DOX) can selectively deliver DOX not only into prostate cancer cells, but into nucleus via targeting integrins β3, thereby significantly improving anticancer effects in 2D prostate cancer cells and 3D tumor spheroids. Particularly, B3int-LS-DOX effectively inhibits tumor growth with an effective dose of as low as 1.5 mg/kg, which is 3.3-fold less than c-RGDyK-LS-DOX (5 mg/kg), indicating that integrins β3 specific therapy is a promising anticancer strategy which can greatly improve the anticancer therapeutic index. In summary, we have identified B3int as the first integrins β3 specific ligand with high affinity and specificity, and holds a great potential of improving the diagnosis and treatment for integrins β3-overexpressed cancers.