Nuclear targeted multimodal 3D-bimetallic Au@Pd nanodendrites promote doxorubicin efficiency in breast cancer therapy

Abstract The therapeutic efficiency of doxorubicin (DOX) is dependent on its sufficient accumulation within the nucleus of cancer cells. Taking advantage of the fascinating properties (e.g., multiple dense arrays of hyperbranches and high surface area) of bimetallic nanodendrites as well as the arginine-rich components of protamine sulfate (PS), we herein present a new type of PS-modified Au@PdNDs-based hydrophobic drug carrier in which DOX can effectively bind to the surface of the PS.Au@PdNDs nanocarrier via non-covalent attachment. Chemical characterization of the synthesized PS.Au@PdNDs.DOX showed the successful loading of DOX onto the surface of PS.Au@PdNDs. Darkfield and Hyperspectral imaging analysis of the PS.Au@PdNDs.DOX demonstrated the time-dependent uptake and prolonged accumulation capability for releasing its DOX cargo inside the nucleus. Specifically, data from the 3D-CytoViva fluorescence imaging did not only track the nanocarrier’s distribution but also confirmed its predominant accumulation in the nuclear compartment through clathrin-mediated endocytosis. Cytotoxicity assay showed that the PS.Au@PdNDs.DOX significantly inhibited cancer cell proliferation with maximum DOX release under acidic conditions (pH 4.5 and 5.5) than at normal physiological pH of 7.4. Moreover, the resultant PS.Au@PdNDs-based DOX nanocarrier efficiently improved the induction of apoptosis in MCF-7 cells compared to free DOX and passive targeted platform. In addition, loss of membrane integrity, mitochondria-apoptotic pathway, and internucleosomal DNA contents from cell cycle progression assay provided insights on the mechanism of cell death. Overall, the PS.Au@PdNDs.DOX nanocarrier may be employed for improved subcellular delivery of DOX as well as multimodal visualization in cancer therapy.