Detection and Treatment of Specific Cancer Cells Using Smart Nanoparticles

Abstract

Developing high-performance, multifunctional nanodevices for cancer (“theranostics”) is a major direction in nanomedicine. Magnetic-plasmonic nanoparticles (NPs) have high potential for medical applications. High surface enhanced Raman scattering (SERS) signals due to suitably shaped plasmonic Au NPs can be used for biological sensing and medical imaging. On the other hand, magnetic Fe3O4 NPs can generate heat under an alternating magnetic field, enabling hyperthermia therapy. Furthermore, a thermo-sensitive material such as poly(N-isopropylacrylamide) (pNIPAm) can be used for drug delivery. Combining Au, a Raman reporter, Fe3O4, pNIPAm, drug and an antibody could form novel nanodevices with both diagnostic and therapeutic functions. HER2-positive breast cancer is a cancer that tests positive for a protein called human epidermal growth factor receptor 2 (HER2), which promotes cancer cell growth. In this investigation, drug-loaded, thermo-sensitive and magnetic-plasmonic Fe3O4@Au@pNIPAm hybrid NPs with HER2 targeting ability were developed (NP diameter: ~50 nm). HER-2/c-erbB-2/neu rabbit polyclonal antibody was conjugated to hybrid NPs for cancer cell targeting. Sensing of HER2-positive cancer cells was provided by high SERS signals that were enabled by hybrid NPs which acted as a SERS-active tag. These hybrid NPs could only be internalized by human breast cancer cells with HER2 (e.g., SK-BR-3 cells), but not by human breast cancer cells without HER2 (e.g., MCF-7 cells). Under a NIR laser or an alternating magnetic field, hyperthermia would occur, causing cancer cell death. Firstly, core-shell structured Fe3O4@Au NPs were made. A pNIPAm coating, which was incorporated with 4-MBA (a Raman reporter) and 5-Fluoroaracil (5-FU, an anti-cancer drug), was produced on Fe3O4@Au. pNIPAm had a lower critical solution temperature (LCST) of 32.3°C. In in vitro release tests, below LCST, only a small amount of 5-FU was released from hybrid NPs. At 42°C, 5-FU was released quickly from hybrid NPs. The viability of SK-BR-3 cells and MCF-7 cells after 48 hrs incubation with hybrid NPs (at various concentrations: 0 to 100 µg/mL) was examined using MTT assay. The hybrid NPs exhibited good biocompatibility even at the NP concentration of 100 µg/mL. Antibody-conjugated hybrid NPs as a stable SERS-active tag for HER2-positive cancer cells were demonstrated. SK-BR-3 cells were detected via strong SERS signals, whereas MCF-7 cells showed little SERS signals. NPs in the right size range accumulated preferentially at SK-BR-3 cells. TEM and LSCM analyses showed that hybrid NPs were successfully internalized by SK-BR-3 cells. In contrast, no cellular uptake of hybrid NPs was observed in MCF-7 cells which are HER2-negtive cells. The hybrid NPs also offered hyperthermia therapy for cancer.