Dual Targeting with Cell Surface Electrical Charge and Folic Acid via Superparamagnetic Fe3O4@Cu2-xS for Photothermal Cancer Cell Killing

There are two critical issues in cancer hyperthermia: (1) photothermal effect and (2) cancer cell targeting efficiency. While the former can be addressed by rendering the nano carriers with significant IR absorptions, the latter is dealt with using a novel dual-targeting strategy. In this study, the Fe3O4 nanoparticle was coated with a shell of Cu2-xS; the resulting Fe3O4@Cu2-xS exhibited strong IR absorption for enhanced photothermal cancer cell killing. The Fe3O4@Cu2-xS nanoparticles are surface functionalized with amphiphilic polyethylenimine (LA-PEI) and Folic acid-TPGS (FA-TPGS) for two purposes: (1) the PEI surface coating renders the particles positively charged, enabling them to effectively bind with negatively-charged cancer cells for more intimate nano/bio contact resulting in much stronger cancer cell ablation; (2) the folic acid modification further increases the targeting efficiency via the folic receptors on the cancer cell surface. Dual-targeting with the surface electrical charge and the tumor-specific folic acid synergistically facilitates both passive and active targeting for significantly improved photothermal killing. A major challenge in cancer therapy is to achieve high cell targeting specificity for the highest therapeutic efficacy. Two major approaches have been shown to be quite effective, namely, (1) bio-marker mediated cell targeting, and (2) electrical charge driven cell binding. The former utilizes the tumor-specific moieties on nano carrier surfaces for active targeting, while the latter relies on nanoparticles binding onto the cancer cell surfaces due to differences in electrical charge. Cancer cells are known for their hallmark metabolic pattern: high rates of glycolysis that lead to negatively charged cell surfaces. In this study, the nanoparticles of Fe3O4@Cu2-xS were rendered positively charged by conjugating their surfaces with different functional groups for strong electrostatic binding onto the negatively-charged cancer cells. In addition to the positively charged surfaces, the Fe3O4@Cu2-xS nanoparticles were also modified with folic acid (FA) for biomarker-based cell targeting. The dual-targeting approach synergistically utilizes the effectiveness of both charge- and biomarker-based cell binding for enhanced cell targeting. Further, these superparamagnetic Fe3O4@Cu2-xS nanoparticles exhibit much stronger IR absorptions compared to Fe3O4, therefore much more effective in photothermal therapy.