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.PhDPharmaceutical SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/116764/1/hpaholak_1.pd
