Molecular imaging with theranostic nanoparticles

Abstract

Nanoparticles (NPs) offer diagnostic and therapeutic capabilities not available with small molecules or microscale tools. As the field of molecular imaging has emerged from the blending of molecular biology with medical imaging, NP imaging is increasingly common for both therapeutic and diagnostic applications. The term theranostic describes technology with concurrent and complementary diagnostic and therapeutic capabilities. Although NPs have been FDA-approved for clinical use as transport vehicles for nearly 15 years, full translation of their theranostic potential is incomplete. However, NPs have shown remarkable success in the areas of drug delivery and magnetic resonance imaging. Emerging applications include image-guided resection, optical/photoacoustic imaging in vivo, contrast-enhanced ultrasound, and thermoablative therapy. Diagnosis with NPs in molecular imaging involves the correlation of the signal with a phenotype. The location and intensity of NP signals emanating from a living subject indicate the disease area's size, stage, and biochemical signature. Therapy with NPs uses the image for resection or delivery of a small molecule or RNA therapeutic. Ablation of the affected area is also possible via heat or radioactivity. The ideal theranostic NP includes several features: (1) it selectively and rapidly accumulates in diseased tissue; (2) it reports biochemical and morphological characteristics of the area; (3) it delivers an effective therapeutic; and (4) it is safe and biodegrades with nontoxic byproducts. Such a system contains a central imaging core surrounded by small molecule therapeutics. The system targets via ligands such as IgG and is protected from immune scavengers by a cloak of protective polymer. Although no NP has achieved all of the above criteria, many NPs possess one or more of these features. While the most clinically translatable NPs have been used in the field of magnetic resonance imaging, other types in development are quickly becoming more biocompatible through methods that modify their toxicity and biodistribution profiles. In this Account, we describe diagnostic imaging and therapeutic uses of NPs. We propose and offer examples of five primary types of nanoparticles with concurrent diagnostic and therapeutic uses.

Figure 1. Evolution of Theranostic NPs

Initial NPs were active in either a therapeutic (delivery) or a diagnostic (imaging) mode. As homing capabilities and multimodal approaches advanced, systems capable of simultaneous therapy and molecular imaging (theranostic) were realized.

Figure 2. Types of NPs

The therapeutic (indicated by red circles) and diagnostic (imaging agent indicated by green flash) roles of nanoparticles (grey scaffold) combine in different fashions. Type I and II are self-contained NPs, while types III and IV involve release of an agent. These NPs may target disease area non-specifically or specifically via homing ligands (indicated by purple wedges). Type V NPs may include various elements of the following four types, however they are only activated in the presence of an external stimulus.

Figure 3. Gold Nanorods

Nanorods have both imaging and therapeutic capabilities as illustrated in a murine model of breast cancer. (A) Gold absorbs X-Rays during CT more strongly than iodine. (B) Nanorods can be used to create a CT map of the tumor. When irradiated with NIR light, the nanorods increase in temperature, which can be mapped via thermal imaging (C). The heating causes tumor death and shrinkage of the tumor (D) resulting in increased survival of treated animals (E). Adapted and reprinted by permission from the American Association for Cancer Research: Reference .

Figure 4. Tracking Injected Cells via Magnetic NPs

Human lymph nodes before (A) and after (B) intranodal injection of iron oxide-labeled cells. Cells could be tracked for 2 days after injection as they traveled through lymphatic system. (C) Magnetic NPs can also be loaded with small molecule therapeutics and immobilized at the disease site via external magnetic field to increase dose. Adapted from reference and .

Figure 5. Quantum Dots

QDs deployed to theranostic applications include the mapping of sentinel lymph nodes (A). 400 pmol of QDs were injected 1 cm deep into living swine tissue. In less than 5 minutes, the QDs have begun to accumulate in the nearest lymph node for image-guided resection. Surgery is continued until all fluorescence (tumor) is removed. (B) Self-illuminating QDs containing a bioluminescent protein and a QD core use coelenterazine substrate to generate signal. Reproduced courtesy of references and .

Figure 6. pH-sentivive NPs

NPs that selectively release paclitaxel in the presence of acidic tumor environment (PbAE-PTX) show statistically (*p<0.05) greater reduction in tumor volume than control NPs or free paclitaxel. Reproduced courtesy reference .