Nanoparticles for biomedical imaging: fundamentals of clinical translation

Abstract

Because of their large size compared to small molecules and their multifunctionality, nanoparticles (NPs) hold promise as biomedical imaging, diagnostic, and theragnostic agents. However, the key to their success hinges on a detailed understanding of their behavior after administration into the body. NP biodistribution, target binding, and clearance are complex functions of their physicochemical properties in serum, which include hydrodynamic diameter, solubility, stability, shape and flexibility, surface charge, composition, and formulation. Moreover, many materials used to construct NPs have real or potential toxicity or may interfere with other medical tests. In this review, we discuss the design considerations that mediate NP behavior in the body and the fundamental principles that govern clinical translation. By analyzing those nanomaterials that have already received regulatory approval, most of which are actually therapeutic agents, we attempt to predict which types of NPs hold potential as diagnostic agents for biomedical imaging. Finally, using quantum dots as an example, we provide a framework for deciding whether an NP-based agent is the best choice for a particular clinical application.

Figure 1. Relative Sizes of Nanoparticles

Hydrodynamic diameter (HD) ranges for nano-scale materials useful for biomedical imaging (top row) and naturally-occurring materials (bottom row).

Figure 2. Physicochemical and Optical Properties of Quantum Dots (QDs) vs. Small Molecules

A. Relative size differences between a 5.5 nm QD (left) and a typical 1 kDa heptamethine indocyanine small molecule NIR fluorophore (right). Shown below each are the ranges in hydrodynamic diameters (HDs) of non-targeted derivatives described in the literature. To the right of each (in orange) are shown the contribution of various targeting ligands, described in the literature, to final HD. B. Summary comparison of key physicochemical and optical properties of inorganic/organic hybrid QDs vs. organic small molecule fluorophores. RES = reticuloendothelial system.

Figure 3. Ultrasmall Zwitterionic Nanoparticles and Their Rapid Renal Clearance after Effective Tumor Targeting

A. Chemical composition of quantum dot QD-CW-cRGD (CW800-conjugated CdSe(CdZnS) QDs with cyclic RGDyK peptide targeting ligands). B. 10 pmol/g of QD-CW-cRGD was injected into tumor-bearing mice and observed at 4 h post-injection. Shown are merged images of color video and NIR fluorescence (pseudo-colored in lime green) acquired using the FLARE™ imaging system. An α_vβ₃-positive M21 tumor (T+) and an α_vβ₃-negative M21-L tumor (T−) are indicated, as are the kidneys and bladder after surgical exposure.