Self-assemblies of cell-penetrating peptides and ferrocifens: design and biological evaluation of an innovative platform for lung cancer treatment.

Chemotherapy, currently used for lung cancer treatment, often consists in a combination of drugs with a moderate efficacy and severe side effects. A major drawback of the classical inorganic drugs used is their hydrophobicity, leading to a very low blood availability and weak efficacy. To overcome this constraint, a nanoplatform was set up in order to vectorize a ferrocifen drug, an organometallic tamoxifen derivative known for its really potent in vitro activity, but as well for its poor water solubility. Two different ferrocifens were tested: P54 and P819. The covalent conjugation of a cell-penetrating peptide (CPP) to the ferrocifen was performed, leading to an amphiphilic prodrug, potentially able to self-assemble. The CPPs used in this study are polyarginines and RLW. Moreover, in order to bring stealth and mucopenetration properties, polyethylene glycol (PEG) was incorporated into the nanostructure. The co-nanoprecipitation of CPP-ferrocifen and PEG-ferrocifen was investigated to achieve self-assemblies. A comparison of the biological activities of different suspensions was performed in vitro on a healthy cell line and on two different lung cancer cell lines. The biological activity of P54 was increased by a factor of 9 with the Arg9-P54 suspension by increasing the cell internalization. Moreover, the P54-based-self-assemblies were chosen to test their in vivo activity on mice bearing lung tumors. The results showed that the intratracheal nebulization of Arg9-P54/PEG-P54 or Arg9-P54 suspensions slowed up significantly the evolution of lung cancer in mice: the suspension with PEG brought an additional comfort to the animal during the administration.