Construction And Evaluation Of Biotinylated Amphiphilic Mixed Micelles For Cancer Treatment

Lung cancer is the leading cause of cancer death world-wide and its treatment remains a challenge in clinic,especially for non-small cell lung cancer(NSCLC).Thus,more effective therapeutic strategies are required for NSCLC treatment.Quercetin(Que)as a natural flavonoid compound has gained increasing interests due to its anticancer activity.However,poor solubility in water,low bioavailability,weak tumor accumulation and short half-life hinder in vivo applications and antitumor effects of Que.In this study,we developed Que loaded mixed micelles(Que-MMICs)assembled from DSPE-PEG-Biotin and PEGMA-PDMAEA-PCL for NSCLC treatment.The results showed that Que was efficiently encapsulated into the mixed micelles and the encapsulation efficiency(EE)was up to 85.7%.Moreover,micelles showed excellent stability without significant size change within 72 h.For over-expressed biotin receptors on A549 cell membrane,biotin conjugation significantly improved 1.2-fold internalization of the carrier compared to that of non-targeted mixed micelles.In vitro results demonstrated that QueMMICs could improve cytotoxicity(IC50=7.83 μg/m L)than Que-MICs(16.15 μg/m L)and free Que(44.22 μg/m L)to A549 cells,which efficiently induced apoptosis and arrested cell cycle.In vivo tumor targeting and antitumor efficiency of these Que formulations were evaluated in A549 tumor xenograft model established in nude BALB/c mice.Di R-MMICs demonstrated much higher accumulation in tumors over in liver and spleen in comparison to Di R-MICs meanwhile no other major organs seemed to be affected.This is ascribed to the combination of EPR effect and active targeting.Due to the potent in vitro antiproliferative activity and in vivo tumor targeting efficiency of Que-loaded micelles,we have the reason to believe that Que-MMICs can efficiently accumulate into tumors and suppress their growth.The Que-MMICs group(TGI=56.7%)showed stronger tumor inhibition activity compared with free Que(TGI=34.8%)and Que-MICs group(43.3%).H&E and TUNEL staining of tumor sections showed that Que loaded induced cell cycle arrest and apoptosis,and the level of Que-MMICs was higher than that of Que-MICs and free Que.In addition,Que-MMICs also reduced the expression of CD31,VEGF and MMP-9 proteins in tumor tissues,suggesting that Que-MMICs can inhibit the formation of tumor blood vessels and the migration and invasion of A549.Collectively,Que-MMICs demonstrated high accumulation at tumor site and exhibited superior anticancer activity in NSCLC bearing mice model.