Preparation And Properties Study Of Folate-conjugated Zein/Fe₃O₄ Nanocomplexes For Targeted Gefitinib Delivery

Chemotherapy is still the most common form of cancer treatment to date.High toxicity,poor aqueous solubility,rapid blood clearence,lack of specificity and acquired resistance are major concerns,which impede the development of many therapeutic anti-cancer agents into safe and effective anti-cancer drugs.To implement accurate,rapid,efficient,low toxicity and even non-toxic treatment,targeted drug delivery system has been developed and widely used.In this work,a dual-targeted drug delivery systems(GEF-FSZs)was prepared by assembling superparamagnetic iron oxide nanoparticles(SPIONs)and anti-cancer drug gefitinib(GEF)into Fa-conjugated zein(Fa-Zein)nanocomplexes.Main contents are as following:(1)Ultrasonic dialysis process(BUDP)was used to prepare GEF-FSZs.After optimizing the operating parameters,i.e.the pH value of dialysate,volume fraction of ethanol-water mixture and ultrasound power,spherical GEF-FSZs with the smallest size of 292±77 nm,good dispersity and high GEF loading efficiency was obtained.The results of TEM,XED,PPMS,~1H-NMR,FT-IR and Uv-vis indicated that Fa was successfully conjugated to Zein,and SPIONs and GEF were both encapsulated into GEF-FSZs without impairing their physico-chemical properties.It was found that the conjugation of Fa and the addition of SPIONs decreased the particle size respectively,while the encapuslation of GEF did not affect the stability of GEF-FSZs.The kinetic model of GEF release from GEF-FSZs revealed that the release of GEF from GEF-FSZs was controlled by the dissolution rate of Fa-Zein,which increased as the pH value decreased.Therefore,GEF-FSZs could be considered as a pH-dependent drug-controlled release system with superior bioavailability of GEF.(2)In vitro cytotoxicity and cellular up-take of GEF-FSZs and other nanocomplexes were assessed against A549 cells.The up-take of water-insoluble GEF was facilitated by encapsulating GEF into a zein-based nanocomplex,and the magnetic responsive property endowed by SPIONs and the conjugation of Fa resulted in enhanced toxicity to A549 cells.The endocytosis study indicated that macropinocytosis and clathrin/caveolae independent endocytosis exerted great influence on the internalization of GEF-FSZs,while GEF was internalized via active transport.These results imply that GEF-FSZs is a promising candidate for targeted drug delivery.