Polysaccharride-based nanocarriers targeting CD44 for lung cancer treatment

Abstract

Introduction Lung cancer is the leading cause of mortality by cancer in the world. There is an urgent need to propose new therapeutic approaches in addition to conventional therapy. To be efficient and to decrease side effects, treatments must specifically reach tumors. In this context, this work aims to develop a new nanocarrier, able to target tumors and to measure its benefit in cancer therapy. The nanoparticles (Np) we used here combine a biodegradable polypeptide, and the Hyaluronan (Hya), the natural ligand of the CD44 receptors upregulated on cancer cells. Methods The ability of Hya fragments with different molecular weights (5000 and 35000 Da), or Np with different sizes (30 and 300 nm), to target the CD44 receptors was studied in vitro using lung cancer cell lines (H358, H460, A549, H322), in which CD44 expression level was measured. We investigated Hya and Np accumulation in tumor in vivo using an orthotopic lung cancer model, after administration by systemic route (IV injections) or pulmonary route (nebulization). We also analysed the accumulation of an anti-CD44 antibody in vivo. Noninvasive optical imaging techniques (2D and 3D fluorescence) allowed the real-time follow-up of the Np in mice. Results Binding of Hya fragments on cell lines was dose-dependent, with a higher affinity for the low molecular weight Hya. Np bound lung cancer cells and were internalized at 37 °C. This interaction was partially dependent to CD44 expression level. In vivo, we observed a better accumulation of the anti-CD44 antibody administered by nebulization, in tumor-bearing mice, compared to healthy mice. In contrast, no specific accumulation of Hya or Np was observed in tumors after nebulization. The nebulized Np showed long time retention in lungs. We observed a higher accumulation of Np, but not Hya, in the lungs of tumor-bearing mice compared to healthy mice, after IV injection. Conclusions We show that CD44 receptor is a pertinent target for lung cancer treatment. Despite the promising results obtained after anti-CD44 antibody nebulization, this way of administration seems less efficient to target tumor with Np. Our results will allow us to select the best Np formulation to load anticancer drugs. We will then evaluate the potential antitumor activity of drug-loaded Np using lung cancer model in mice.