The Development of Theranostic Agents for Photoacoustic Detection and Laser-activated Anti-HER2 Breast Cancer Therapy

Abstract

<p>Breast cancer is one of the most common malignancies among women. Mammography and ultrasound imaging modalities are routinely used as breast cancer screening procedures. The sensitivity of those modalities decreases significantly in patients with dense tissues and advanced stage breast cancer. Photoacoustic (PA) imaging, as a non-invasive modality, may offer increased sensitivity for screening breast tumors. To probe additional, specific structural and molecular information, targeted exogenous contrast agents are often introduced. Gold nanorods (GNRs) are effective contrast agents in PA imaging due to their high optical absorption at the near-infrared band and superior biocompatibility. The high spatial localization of GNRs provides significant increases in signal amplitude within the target tissue and assists nanoparticle-mediated cancer therapy. I proposed using targeted theranostic agents containing GNRs for breast tumour detection using a photoacoustic method and laser-activated therapy. In this work, I have developed polymeric nanoparticles (NPs) for the imaging and treatment of breast cancer over-expressing human epidermal growth factor receptor 2 (HER2). These NPs contain a perfluorohexane liquid and gold nanorods (GNRs) interior stabilized by biodegradable and biocompatible copolymer PLGA-PEG. Water-insoluble therapeutic drug Paclitaxel (PAC) and fluorescent dye are encapsulated into the PLGA shell. The NP surfaces are conjugated to the HER2-binding antibody Herceptin to target HER2-positive cancer cells actively. The NP uptake by tumor is evaluated using multi-spectral PA imaging. The effectiveness of cancer cell treatment by laser-induced particle vaporization and stimulated drug release are investigated in vitro. The therapeutic efficacy on tumours is also performed using a xenograft mouse bilateral tumor model. PA quantitative analysis demonstrates that these NPs actively target HER2 positive cells with high efficiency. The laser-induced vaporization causes more damage to the targeted cells versus PAC-only and negative controls. The relative concentrations of GNRs in the tumour with peak signal at 6 hours are quantified using a linear spectral unmixing technique. The therapeutic efficacy of these nanoparticles is evaluated using tissue immunofluorescence and histology. In this dissertation, PLGA-PEG-GNRs as theranostic agents for anti-HER2 breast cancer therapy are developed. They may provide better diagnostic imaging and therapeutic potential than current methods for treating HER2-positive breast cancer.</p>