Aerosol delivery of immunotherapy and Hesperetin-loaded nanoparticles increases survival in a murine lung cancer model.

Purpose: Studies have shown that flavonoids like Hesperetin, an ACE2 receptor agonist with antioxidant and pro-apoptotic activity, can induce apoptosis in cancer cells. ACE2 receptors are abundant in lung cancer cells. Here, we explored the application of Hesperetin bound to PLGA-coated nanoparticles (Hesperetin-nanoparticles, HNPs), and anti-CD40 antibody as an aerosol treatment for lung tumor-bearing mice. Methods: Results: Analysis of an orthotopic murine lung cancer model demonstrates a differential uptake of the HNP and anti-CD40 by cancer cells relative to normal cells. A higher survival rate, relative to untreated controls, was observed when aerosol treatment with HNP was added to treatment via anti-CD40 (p<0.001), as compared to CD40 alone (p<0.01). Moreover, 2 out of 9 tumor-bearing mice survived long term, and their tumors diminished. These 2 mice were shown to be refractory to subsequent development of subcutaneous tumors, indicating systemic resilience to tumor formation. Conclusion: We successfully established increased therapeutic efficacy of anti-CD40 and HNP in an orthotopic murine lung cancer model using inhalation-based administration. Our findings open the possibility of improved lung cancer treatment using flavonoids and immuno-adjuvants.