Dual-Targeted Nano-in-Nano Albumin Carriers Enhance the Efficacy of Combined Chemo/Herbal Therapy of Lung Cancer

Aim: A Nano-in-Nano approach was exploited to facilitate incorporation of the chemotherapeutic drug etoposide (ETP) as nanosuspension, synergistically with berberine (BER) into hydrophilic albumin nanoparticles (HSA NPs).Methods: For maximal tumor targeting, HSA was modified with mannose and phenyl-boronic acid. Furthermore, different crosslinkers were investigated for sustained release of water soluble BER from HSA NPs. Results: The elaborated dual-targeted HSA NPs (216.2 nm) were spherical with high BER and ETP entrapment efficiency (69.5 and 87.6%, respectively) and loading (10.52 and 14.04%, respectively). The NPs exhibited sequential release pattern for both ETP and BER (51.55 and 34.33% over 72 h, respectively). Phenyl-boronic acid/mannose-HSA NPs demonstrated powerful cytotoxicity against A549 lung cancer cells (IC50: 12.4 μg/ml) correlated to enhanced cellular internalization. Dual-targeted NPs displayed 9.77-fold higher caspase-3 level and 3.5-fold lower VEGF level than positive control mice. Conclusion: Dual-targeted Nano-in-Nano albumin carriers could be beneficial for parenteral ETP/BER delivery to lung cancer.