Gold Nanostars For Cancer Molecular Imaging and Therapy
Gold nanostars (AuNS) have been utilized in cancer imaging and therapeutics for over decade due to the tunability of their optical resonance in the near-infrared, which allows deep tissue penetration, as well as their ability to convert light to heat. The geometry of the AuNSs is key to these functions where the nanostars core absorbs incident light and the protrusions generate strong electromagnetic fields. The utility of these enhanced fields has been shown both in surface enhanced Raman spectroscopy (SERS) generating strong spectral enhancement in vivo, as well in photothermally mediated drug delivery. In this thesis, I will demonstrate the design, synthesis, and application of AuNSs for cancer chemo-photothermal combination therapy where hyperthermia generated by AuNS triggered the release of anticancer drug doxorubicin from thermosensitive liposomes. The synergism of the two therapeutic approach induced cytotoxicity in drug-resisting triple negative breast cancer cells with higher efficacy than the unencapsulated drug alone, which is the current clinical standard. Next, the AuNS was combined with SERS to detect biomarkers of cancer in vivo to ultimately provide a rapid molecular imaging platform for screening and for patient selection for immunotherapies. I demonstrated the multiplexed detection of both programmed cell death ligand 1 (PD-L1) and epidermal growth factor receptor (EGFR), biomarkers elevated in breast cancer in vitro and in vivo. Time-dependent SERS imaging showed highly specific and sensitive detection with high spatiotemporal resolution. In vivo endpoints was quantified ex vivo with SERS maps of whole tumor lesions receptor-targeted distribution of AuNSs with cellular-level resolution. Further, I modified AuNSs to achieve multiplexed detection of both immune cells and tumors cells by targeting CD8+ T cells and PD-L1 combining SERS with positron emission tomography (PET), a clinical imaging approach. Synergistic ImmunoPET-SERS imaging allowed depth-resolved whole body imaging identifying melanoma tumors with PET and multiplexed molecular information of PD-L1 and CD8 levels in real time in tumors with SERS. Using this approach, we also demonstrated their ability to monitor response to treatment of mice treated with combinatorial immunotherapies. Mice treated with CD137 and PD-L1 therapy showed an elevation in CD8+ T cells infiltration, which was successfully observed by PET/SERS. Ultimately the molecular information of the tumor can be used to provide an accurate prognosis and optimal immunotherapy treatment plan to achieve high response rate in cancer therapy. Overall, I have designed AuNS for cancer chemo-photothermal therapy and for multiplexed SERS or SERS/PET imaging to detect cancer-specific receptors. Significant future works can be built based on the work I have conducted here. The therapeutic and imaging platform are not cancer specific and should be investigated for different disease models.