Tat-functionalized Ag-Fe3O4 nano-composites as tissue-penetrating vehicles for tumor magnetic targeting and drug delivery

Abstract

In this paper, we prepared a dual functional system based on dextrin-coated silver nanoparticles which were further attached with iron oxide nanoparticles and cell penetrating peptide (Tat), producing Tat-modified Ag-Fe3O4 nanocomposites (Tat-FeAgNPs). To load drugs, an –SH containing linker, 3-mercaptopropanohydrazide, was designed and synthesized. It enabled the silver carriers to load and release doxorubicin (Dox) in a pH-sensitive pattern. The delivery efficiency of this system was assessed in vitro using MCF-7 cells, and in vivo using null BalB/c mice bearing MCF-7 xenograft tumors. Our results demonstrated that both Tat and externally applied magnetic field could promote cellular uptake and consequently the cytotoxicity of doxorubicin-loaded nanoparticles, with the IC50 of Tat-FeAgNP-Dox to be 0.63 µmol/L. The in vivo delivery efficiency of Tat-FeAgNP carrying Cy5 to the mouse tumor was analyzed using the in vivo optical imaging tests, in which Tat-FeAgNP-Cy5 yielded the most efficient accumulation in the tumor (6.7±2.4% ID of Tat-FeAgNPs). Anti-tumor assessment also demonstrated that Tat-FeAgNP-Dox displayed the most significant tumor-inhibiting effects and reduced the specific growth rate of tumor by 29.6% (P = 0.009), which could be attributed to its superior performance in tumor drug delivery in comparison with the control nanovehicles. KEY WORDS: Cell penetrating peptide, Tat, Silver nanoparticles, Magnetic targeting, Fe3O4, Hydrazone bond