Non-small cell lung cancer combination therapy: Hyaluronic acid modified, epidermal growth factor receptor targeted, pH sensitive lipid-polymer hybrid nanoparticles for the delivery of erlotinib plus bevacizumab.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality in China. This study aimed to develop a hyaluronic acid (HA) decorated, pH sensitive lipid-polymer hybrid nanoparticles (LPH NPs) to co-deliver erlotinib (ERL) and bevacizumab (BEV) (HA-ERL/BEV-LPH NPs) for targeting and suppressing NSCLC. HA contained pH sensitive nano-materials were synthesized by acylation reaction. HA-ERL/BEV-LPH NPs were prepared using a sonication method. To explore the efficiency of the system, we evaluated the physicochemical parameters and performed a release study, a cellular uptake assay, a cytotoxicity evaluation, and several in vivo anti-tumor studies in comparison with free drugs and single drug systems. All LPH NPs samples have particle sizes of about 100-120 nm, polydispersity index values range from 0.12 to 0.15, and negative zeta potentials. HA-ERL/BEV-LPH NPs contained pH sensitive adipic acid dihydrazide (ADH) showed fast drug release at pH 5.5 than pH 7.4. After 21 days, the tumor volume of the HA-ERL/BEV-LPH NPs group (229.2 ± 13.1 mm3) was significantly smaller than 0.9 % NaCl control group (1126.3 ± 39.4 mm3), with a tumor inhibition rate of 79.7 ± 3.2 %. The maximum plasma ERL concentrations, half life period, and area under the curve of HA-ERL/BEV-LPH NPs were 21.6 μg/mL, 7.57 h, and 290.3 mg/L·h). With the highest tumor tissue accumulation concentration (25.3 μg/mL) and low system toxicity, HA-ERL/BEV-LPH NPs. HA-ERL/BEV-LPH NPs could be used as a promising system for the combination therapy of NSCLC.