A Study of Multi-modal Theranostic Particle Systems for Biological Applications

Abstract

Theranostic particles, which have a dual capacity for diagnosis and therapeutics, activated by ultrasound have emerged as a novel concept for disease detection and treatment. Also, the approach could overcome intrinsic mismatch of key metrics (e.g., pharmacokinetics, selectivity, biodistribution) between imaging and therapeutic agents, thereby allowing for precise, imaging-guided drug delivery. The technology could also open up a new opportunity for rapid assessment and adjustment of treatment regime, based on real-time imaging feedback during therapy. Many different types of theranostic agents have been developed using magnetic nanoparticles, quantum dots or novel metal nanoparticles as substrates. Existing detection modalities (e.g., magnetic resonance imaging, optical excitation) could be used to image these agents with high contrast, and often to actuate them for drug release. Most of the developed theranostic agents, however, are still difficult to be translated into clinical applications. A significant concern is the potential toxicity of constituent materials (e.g., metal or semiconductor nanoparticles). Some agents also require specialized equipments, besides imaging instruments, to release therapeutic materials (e.g., magnetic hyperthermia, photodynamic therapy). Microbubble (micro-meter sized bubble, MB) and liposome (Lipo) particles, conversely, are promising clinical application materials comprising non-toxic lipid chemicals. These newly developed materials can be used for the diagnosis and treatment of cancer and serve as alternatives to conventional theranostics that have known toxicological problems. Synthesized with biocompatible polymers, these particles are shown to be non-toxic for in vivo uses. They can also be loaded with contrast agents for enhanced imaging (e.g., microscopy, MRI, ultrasound), and importantly, with therapeutic materials to treat tumor. To assess their potential in biological applications, the following chapters were studied. The first theme herein introduces a microbubble and liposome complex (MB-Lipo) developed for ultrasound (US) imaging and activation. The MB-Lipo particles have a hybrid structure consisting of a MB complexed with multiple Lipos. The MB components are used to generate high echo signals in US imaging, while the Lipos serve as a versatile carrier of therapeutic materials. MB-Lipo allows high contrast US imaging of tumor sites. More importantly, the application of high acoustic pressure bursts MBs, which releases therapeutic Lipos and further enhances their intracellular delivery through sonoporation effect. Both imaging and drug release could thus be achieved by a single US modality, enabling in situ treatment guided by real-time imaging. The MB-Lipo system was applied to specifically deliver anticancer drug and genes to tumor cells, which showed enhanced therapeutic effect. This theme also demonstrates the clinical potential of MB-Lipo by imaging and treating tumor in vivo. The second theme explains how the scope of the existing application is broadened. A hybrid multifunctional particle comprising of a MB, Lipo, and an Fe ion chelated melanin nanoparticle (MNP (Fe)) was applied for ultrasound mediated cancer targeting as a theranostic agent. Also, MNP (Fe) has this hybrid multifunctional particle diagnose cancer cells. The third theme elucidates that optimization of parameters of portable US generator can promote development in delivery of hydrophobic and hydrophilic therapeutic materials into cancer cells. In summary, MB has an outstanding US diagnosis function of cancer and MB burst indeed improved the co-delivery of therapeutic agents and MRI contrast agent.