To reduce premature drug release while ensuring burst intracellular drug release of solid lipid nanoparticle-based drug delivery system with clathrin modification

• Published in: Nanomedicine 2019-01, Vol.15 (1), p.108-118
• Main Authors: Li, Jingcao, Sun, Lan, Liu, Yan, Yao, Hongjuan, Jiang, Shuang, YunzhuPu, Li, Yajuan, Zhang, Yingge
• Format: Article
• Language: English
• Subjects: Clathrin; Intracellular drug delivery; Mechanical strength; Nanoscale drug delivery system; Salinomycin
• ISSN: 1549-9634; 1549-9642
• DOI: 10.1016/j.nano.2018.05.014

Nanoscale drug delivery system (NDDS) with slow premature drug release (PDR) while ensuring burst intracellular drug release (BIDR) is becoming a hot point in NDDS-based nanomedicine. Here we used clathrin to modify a solid lipid nanoparticle (SLN)-based NDDS of salinomycin (SLN-SAL) to prepare NDDS with reduced PDR while ensuring BIDR. Drug-release-kinetic experiments revealed that clathrin modified SLN-SAL (CMSLN-SAL) reduced PDR while ensured BIDR of its prototype NDDS, SLN-SAL. Mechanism experiments revealed that clathrin modification reduced PDR of SLN-SAL through increasing the mechanical strength of SLN-SAL and ensured BIDR of SLN-SAL through lipid membrane fusion after its clathrin shell was de-polymerized by a cytoplasm enzyme, HSC70. In addition, CMSLN-SAL had significantly higher intracellular uptake and stronger inhibitive effects on cancer cells than that of SLN-SAL. These results demonstrated that clathrin modification is an effective way to reduce PDR while ensuring BIDR and increasing the anticancer effects of SLN-based NDDS. The clathrin-shell of clathrin-modified solid lipid nanoparticle-based nanoscale drug delivery system of salinomycin (CMSLN-SAL) works as a cable net to resist internal osmotic pressure to block particle expending and as a cage-like scaffold to resist external pressure exerted by the blood flow at the artery bifurcation and the mouth piece of vascular clefts to block particle deformation, and thereby to reduce the drug loss in transportation, namely, the premature drug release. In tumor cells, the clathrin shell of CMSLN-SAL is depolymerized by HSC70 and the inner SLN-SAL is freed in cytosol to ensure the intracellular burst drug release. [Display omitted]