Imaging and drug delivery using theranostic nanoparticles

Abstract

Nanoparticle technologies are significantly impacting the development of both therapeutic and diagnostic agents. At the intersection between treatment and diagnosis, interest has grown in combining both paradigms into clinically effective formulations. This concept, recently coined as theranostics, is highly relevant to agents that target molecular biomarkers of disease and is expected to contribute to personalized medicine. Here we review state-of-the-art nanoparticles from a therapeutic and a diagnostic perspective and discuss challenges in bringing these fields together. Major classes of nanoparticles include, drug conjugates and complexes, dendrimers, vesicles, micelles, core–shell particles, microbubbles, and carbon nanotubes. Most of these formulations have been described as carriers of either drugs or contrast agents. To observe these formulations and their interactions with disease, a variety of contrast agents have been used, including optically active small molecules, metals and metal oxides, ultrasonic contrast agents, and radionuclides. The opportunity to rapidly assess and adjust treatment to the needs of the individual offers potential advantages that will spur the development of theranostic agents.

Introduction

Medical nanotechnology has been developing for decades, and innovative applications are coming to fruition [1]. Nanoparticle formulations, such as Doxil^TM and Abraxane^TM, have demonstrated clinical relevance by increasing drug efficacy and decreasing toxicity, and numerous targeted formulations are under clinical evaluation [2], [3]. Some promising applications use nanometer-scale particles for simultaneous drug delivery and molecular imaging. There are unique opportunities to use multifunctional formulations for both diagnostic and therapeutic purposes. This review focuses on the inherent feasibility and practicality of this concept.

Currently, the term ‘theranostics’ encompasses two distinct definitions. We focus on theranostics as defined by the combination of therapeutic and diagnostic agents on a single platform. Specifically, we explore the development of theranostic nanoparticles (TNPs) that may simultaneously monitor and treat disease. A slightly broader definition has also been proposed, whereby theranostics is defined by use of an appropriate diagnostic methodology to personalize a separate therapeutic intervention [4]. Due to the widespread use of diagnostic tools in clinical decision-making, we have focused on the narrower definition. TNPs offer opportunities to combine passive and active targeting, environmentally-responsive drug release, molecular imaging, and other therapeutic functions into a single platform.

The engineering of multifunctional TNPs will not be straightforward; furthermore, instructive lessons can be gleaned from nearly a half-century of research on nanoparticulate drug carriers. Potential obstacles to successful TNPs include the discovery and targeting of new biomarkers, the innate toxicity of the nanoparticle components, formulation stability, production costs, and control of intellectual property [5], [6]. As these new formulations arise, so do large knowledge gaps regarding the safety of nanoparticulates [7]. In addition, optimal therapeutics and diagnostics are two very different entities. Diagnostic (or contrast) agents serve to enhance visibility of specific tissues by increasing the signal to noise ratio relative to surrounding tissues and are generally optimized to provide a quick, high-fidelity snapshot of the living system. Depending upon the wash-in/wash-out kinetics and clearance times of the agent, either a low or high molecular weight (fast or slow clearing) contrast agent can be used [8]. Therapeutic nanoparticle formulations that have been used clinically are commonly long-circulating. This potential discrepancy between fast and slow clearance rates must be reconciled to develop clinically useful TNPs.

The development of effective TNPs will require some give and take between imaging sensitivity, accuracy of targeting, and controlled drug release. Via a host of materials, many pathways are being explored to reach these goals. Currently, the modalities available for imaging of TNPs include optical imaging, magnetic resonance imaging (MRI), nuclear imaging, computed tomography (CT), and ultrasound (US) [9]. Each imaging modality and TNP has relative advantages and disadvantages, which will be discussed.