Development of theranostics nanomaterials

Abstract

Clinical outcomes of conventional anticancer therapies are often compromised due to off-target toxicity and adaptive drug resistance. Moreover, currently there are no imaging modalities that can be utilized for real-time monitoring of therapeutic responses in the human body. Therefore, there is a critical need to develop a novel generation of personalized medicine that combines functionalities of diagnosis and therapy, with an ultimate goal of early detection, accurate treatment and timely assessment of therapeutic efficacy. Over the last few decades, a variety of nano-medical materials or devices such as liposomes, micelles, quantum dots, magnetic nanoparticles and plasmonic nanobubbles have been developed to deliver therapeutic products or diagnostic agents to the sites of disease in a controlled manner with reduced or eliminated side effects to normal tissues. This dissertation focuses on the development of functional molecular imaging probe and nanoparticles-based therapeutic agent delivery systems for effective theranostics of lymphatically metastatic cancer, thus opening new avenues to combat cancer. In chapter 2, a near-infrared (NIR) absorbing dye -based caspase-9 image probe was synthesized in 11 steps to directly detect apoptotic cells with high specificity. This cell-permeable molecular contrast agent has demonstrated the feasibility of monitoring cancer cell apoptosis induced by chemotherapeutics in mice bearing head and neck squamous cell carcinoma (HNSCC), via non-invasive photoacoustic imaging (PAI) within 24 h after treatment, thus to predict treatment efficacy. In chapter 3, a biocompatible core/shell FePt@Fe3O4 magnetic nanoparticles (MNPs) was developed as a robust probe for magnetic resonance imaging (MRI) and to mediate hyperthermia treatment against breast tumor. Enhanced anti-tumor effectiveness was demonstrated in a mouse model of 4T1.2 Neu breast tumor as a consequence of the high magnetic-thermal energy transfer capability of MNPs. In addition, increased MRI contrast in the tumor region potentiated the clinical application of MNPs for cancer diagnosis. In chapter 4, Cabozantinib (XL-184), a poorly water-soluble pan-kinase inhibitor, was encapsulated into a DSPE-PEG2000 micellar formulation with excellent colloidal stability. Compared with the free XL-184 solution, drug-loaded micelles exhibited increased intracellular drug uptake and higher cytotoxicity in one human lung adenocarcinoma epithelial cell line and two human malignant glioblastoma cell lines. In chapter 5, a high molecular-weight hyaluronic acid-deferoxamine (DFO) conjugated was synthesized for sustained release delivery of DFO, whose potent iron-chelating capability can be utilized to reverse the radiotherapy-induced pathologic effects. The HA-DFO conjugate exhibited significantly decreased cytotoxicity to normal cells and excellent biodegradability. In addition, localized HA- DFO injection stimulated vascularity and improved bony regeneration and union after radiotherapy. In chapter 6, a nano-hyaluronic acid (HA)-based anticancer drug, HA- Cisplatin, was subcutaneously injected in an in-vivo murine model for locally advanced melanoma. Compared with the untreated control group and cisplatin- treated group (intravenous or subcutaneous injection), significant tumor shrinkage was observed in the subcutaneous peri-tumoral HA-cisplatin group, offering great potential as a therapeutic option in the treatment of certain types of human melanoma.