The field of theranostics (a portmanteau of “therapeutics” and “diagnostics”) aims to integrate therapeutics with diagnosis, in order to develop more individualized therapies. Life-threatening diseases, particularly high-risk cancers, are highly heterogeneous, so that treatments are typically effective for only limited patient populations and at certain stages of disease development. Merging of the paradigms of diagnosis and therapy will provide timely assessment of therapeutic response, allowing optimization of treatments and tailoring personalized medicine based on individual needs, to improve therapeutic outcomes. A current clinical example is the use of Herceptin^® (a monoclonal antibody used to treat patients with breast cancer), which is used in conjunction with the diagnostic tool, HercepTest^®. Herceptin^® targets the HER2 protein, which is overexpressed in approximately one-third of breast cancers. HercepTest^™ specifically demonstrates overexpression of the HER2 protein in breast cancer tissues and so is used to identify those patients who are most likely to benefit from Herceptin^® treatment.

Currently, research activities on theranostics are predominantly focused on cancer diagnosis and treatment. Cancer is the third most common cause of death in the world, following cardiovascular and infectious diseases. There are significant challenges in the successful delivery of cytotoxic drugs specifically to tumor cells while avoiding normal healthy tissues and minimizing side effects. In addition, it is essential to carry out diagnostic imaging to understand the cellular phenotypes, biological activity, and heterogeneity of each tumor. In response to these challenges, theranostics offers the potential to allow physicians to monitor the drugs given to each patient while assessing drug pharmacokinetics and biodistribution, as well as tumor response, all in a noninvasive and real-time manner. As a result, physicians will be able to avoid the prolonged use of nonresponsive therapies to treat cancer; instead, they will be able to alter or design innovative treatment regimens, tailored to each individual case, to improve overall survival.

Various types of medical imaging procedures allow the evaluation of organ functions and assist in the diagnosis of disease. Many of these imaging procedures are now being investigated for their application to theranostics.

Magnetic resonance imaging (MRI) produces images by measuring the radio-frequency signals that are given off by magnetized protons in living tissue. Image contrast of different tissues is created because protons in each tissue possess their own characteristic magnetic properties. Image contrast also can be enhanced with the aid of contrast agents that are delivered into the tumor tissue. Contrast agents are paramagnetic materials that can alter the magnetic properties of water protons to enhance the signal in the tissue of interest and help delineate it from that of the normal surrounding tissue. MRI is a beneficial imaging technique because it offers high spatial resolution without any tissue-penetrating limitations. Currently, highly stable gadolinium (Gd) complexes are commonly used to produce bright signal enhancement, while paramagnetic iron oxide nanoparticles (IONPs) generate dark signal enhancement.

Computed tomography (CT) is one of the most commonly used modalities in diagnostic imaging–based x-ray attenuation. CT provides superior visualization of structures with high densities but is limited when used to distinguish soft tissues that have similar densities. CT contrast agents are introduced in order to improve image contrast of soft tissue structures with similar or identical densities. CT contrast agents are composed of biocompatible materials containing elements of high atomic numbers. Clinical CT contrast agents are generally iodinated compounds. NPs containing high-atomic-number elements, such as gold, are now being investigated as CT contrast agents.

Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are nuclear imaging techniques used to map physiological and biological processes in the body following the administration of radiolabeled tracers. In PET, positrons (positively charged electrons) emitted from the nucleus during decay travel a few millimeters in the tissue, where they undergo annihilation by colliding with electrons. Each annihilation event releases two gamma-ray photons of equal energy (511 keV) in opposite trajectories (180° apart). PET scanners utilize the simultaneous detection of these two photons to precisely locate the source of the annihilation event. Positronemitting isotopes ¹⁵O, ¹³N, ¹¹C, ¹⁸F, ⁶⁴Cu, ⁶²Cu, and ⁶⁸Ga are often incorporated into biorelevant materials to follow their distribution and concentration, and to detect malignant diseases. SPECT employs gamma-emitting isotopes, such as ^99mTc, ¹¹¹In, and ¹²³I, as probes to detect biomarkers and to label NPs. SPECT imaging can quantitatively determine disease-related biomarkers for diagnostic imaging, to track biodistribution of NPs and to assess therapeutic efficacy.

Optical imaging utilizes photons of a characteristic wavelength to excite fluorescence materials, to visualize biomarkers and to study the localization of materials. Optical imaging offers a high sensitivity and the capability of multicolor imaging. A major limitation of optical imaging is the small depth of light penetration, ranging from hundreds of microns to several centimeters. Near-infrared (NIR) imaging has proven to be more desirable owing to better tissue penetration and less interference from tissue autofluorescence.

Gold nanoparticles (AuNPs) have emerged as one of the most extensively investigated theranostic platforms for the diagnosis, imaging, monitoring, and treatment of malignant and other diseases. AuNPs possess a variety of advantageous properties that make them very useful as multifunctional theranostic vehicles. AuNPs offer inherent biological compatibility, an important advantage over many other synthetic delivery systems described later. Furthermore, their large surface area means they can serve as highly efficient carriers, capable of high drug and diagnostic loading. Using simple wet-laboratory techniques, gold nanocarriers have been constructed in a variety of shapes and sizes, including spheres, cubes, rods, cages, and wires; all of which can now be prepared with accurate quality control and in large quantity. They can also be used as either the core or the shell, for polymer–metal and metal–metal hybrid NPs.

AuNPs have high atomic number and induce strong x-ray attenuation, making them effective contrast agents for CT imaging. Because AuNPs are visible by CT, they have potential to be noninvasively assessed in pharmacokinetics, biodistribution, and tumor targeting. AuNP-based theranostics are often developed by surface modification with therapeutic agents and other imaging agents. Photosensitizers (PS), dyes, drugs, and targeting ligands can all be attached to the surface of AuNPs either directly, via amine or thiol groups, or indirectly, using a linker molecule such as bovine serum albumin. Other imaging agents, such as Gd chelates for use in MRI, and radioisotopes for nuclear medicine, are attached to AuNPs for multimodal imaging and image-guided therapy.

Encouraging preclinical data is accumulating on the use of AuNPs as theranostic agents. Chen et al. have recently synthesized and characterized folic acid–functionalized, dendrimer-entrapped AuNPs containing the MRI agent Gd, thereby developing a nanoprobe suitable for both CT and MRI methodologies (Chen et al. 2013). The AuNPs were entrapped within the dendrimer interior and the Gd was modified on the dendrimer surfaces. This multifunctional construct specifically targeted folic acid receptor–expressing cancer cells via a receptor-mediated pathway. Both in vitro cell imaging and in vivo tumor imaging demonstrated significantly improved contrast-to-noise ratios, indicating the potential of this system to detect cancer cells in the body using dual-mode CT/MRI.

IONPs are made from magnetite (Fe₃O₄). IONPs less than 20 nm are superparamagnetic (i.e., the particles show zero magnetism in the absence of an external magnetic field but can become magnetized in the presence of one) and can be used as contrast agents in MRI. Unlike Gd-based contrast agents, superparamagnetic iron oxide nanoparticles (SPIONs) decrease MR signals of surrounding water protons, resulting in dark signal enhancement. SPIONs are extensively investigated for theranostic purposes. SPIONs need to be surface-engineered to improve their solubility, stability, and performance in vivo. SPIONs are typically coated with hydrophilic materials. A wide variety of coating materials have been used for SPION modification, including dextrans, dendrimers, and polyvinylpyrrolidone. Therapeutics and targeting agents have been covalently conjugated to SPIONs. Biodegradable spacers, e.g., peptides, have been used to facilitate drug release in response to the environment, e.g., within lysosomes. This ensures release of the drug into the cytosol of cells, upon reaching the acidic endosome/lysosome compartments after cellular uptake (Kohler et al. 2005). Small-sized SPIONs are often incorporated into other larger drug carriers, including liposomes, polymersome, polymeric NPs, and silica NPs, to enable visualization of the larger carriers noninvasively with MRI.