| Rapid advances in bioinformatics and nanotechnology have sparked pre-clinical development of innovative therapies with potential to transform approaches to non-specific clinical practices such as chemotherapy and radiation. One of few nanoparticle-based treatments in clinical trials is photothermal therapy (PTT), which is localized by near infrared light activation of heat-producing gold nanoshells. Here we demonstrate nanoparticle-mediated PTT as a multifunctional platform to address key challenges of cancer medicine, to improve patient tolerance and long-term survival. We present our work in two sections: enhancing efficacy in metastatic settings, and increasing specificity to reduce associated toxicity.;In the first section, we focus on the efficacy of PTT against breast cancer stem cells (BCSCs) and tumor-mediated immunosuppressive signaling -- vital drivers of cancer growth and metastasis. First we study PTT via highly crystallized iron oxide nanoparticles (HCIONPs) in human breast cancer cells in immune-compromised mice. PTT inhibits both epithelial-like (ALDH+) and mesenchymal-like (CD44+/CD24-) BCSCs and BCSC-driven secondary tumor formation. PTT prior to surgery prevents lymph node metastasis. Next we evaluate HCIONP-mediated PTT and cancer immunotherapy (PD-L1 antibody) in immune-competent mice. PTT significantly reduces mouse ALDH+ BCSCs when given alone and in combination with PD-L1 antibody. Combination treatment reveals promising reductions in tumor growth and formation of lung macrometastases. Furthermore, increases of key inflammatory cytokines and immune cell-attracting chemokines suggest the potential to enhance T-cell tumor infiltration to trigger a systemic, cancer (stem) cell-specific immune response.;In the second section, we focus on development of optimized targeted nanoparticle formulations, applicable for PTT, to improve specificity and efficiency of cancer therapy. First we report a new technique -- 'living' PEGylation -- to control the density and composition of heterobifunctional poly(ethylene glycol) (HS-PEG-R) on gold nanoparticles. Applications we demonstrate include control of targeting ligand (HS-PEG-RGD) density to maximize nanoparticle targeting efficiency, and development of double-charged, stealthy nanoparticles (optimal HS-PEG-NH2:HS-PEG-COOH ratio) to minimize immune cell uptake. Lastly, we describe targeted, theranostic nanocomposites with a core-satellite structure for PTT and magnetic resonance imaging. A facilely produced "clickable" targeting peptide enables precise control over attachment to the nanoparticles to prevent steric hindrance and optimize binding to the target receptor. |
