Combinatory Delivery of Etoposide and siCD47 in a Lipid Polymer Hybrid Delays Lung Tumor Growth in an Experimental Melanoma Lung Metastatic Model.

Abstract

This study investigated the feasibility of lipid polymer hybrid nanoparticles (LPH) as a platform for the combinatorial delivery of small interfering RNA (siRNA) and etoposide (Eto). Different Eto loaded LPH formulations (LPHEto ) are prepared. The optimized cationic LPHEto with a particle size of 109.66 ± 5.17nmand Eto entrapment efficiency (EE %) of 80.33 ± 2.55is used to incorporate siRNA targeting CD47 (siCD47), a do not eat me marker on the surface of cancer cells. The siRNA-encapsulating LPH (LPHsiNEG-Eto ) has a particle size of 115.9 ± 4.11nm and siRNA EE % of 63.54 ± 4.36 %.LPHs improved the cellular uptake of siRNA in a dose- and concentration-dependent manner. Enhanced cytotoxicity (3.8-fold higher than Eto solution) and high siRNA transfection efficiency (≈50 %) are obtained. Anin vivobiodistribution study showed a preferential uptake of the nanosystem into lung, liver, and spleen. In an experimental pseudo-metastatic B16F10 lung tumor model, a superior therapeutic outcome can be observed in mice treated with combinatory therapy. Immunological studies revealed elevated CD4+, CD8+ cells, and macrophages in the lung following combinatory treatment. The study suggests the potential of the current system for combinatory chemotherapy and immunotherapy for the treatment of lung cancer or lung metastasis.