Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities

Abstract

Nanoparticle-based drug delivery systems have been developed to improve the efficacy and reduce the systemic toxicity of a wide range of drugs. Although clinically approved nanoparticles have consistently shown value in reducing drug toxicity, their use has not always translated into improved clinical outcomes. This has led to the development of "multifunctional" nanoparticles, where additional capabilities like targeting and image contrast enhancement are added to the nanoparticles. However, additional functionality means additional synthetic steps and costs, more convoluted behavior and effects in vivo, and also greater regulatory hurdles. The trade-off between additional functionality and complexity is the subject of ongoing debate and the focus of this Review.

Figure 1

Schematic of a multifunctional nanoparticle. Multifunctional nanoparticles can be prepared with a wide range of therapeutic, imaging, and targeting agents. Representative examples are shown, with relative expenses indicated by dollar symbols. The addition of each new functionality is expected to have a beneficial impact on patient survival; however, this will come at the cost of additional regulatory, production, and financial hurdles. The trade-off between these “costs” and clinical benefit will be highly dependent on the choices made when designing multifunctional nanoparticles. The following agents are shown: Targeting (left: folic acid, center: antibody, right: aptamer); Imaging (top: chelated Technetium-99m, center: chelated gadolinium, bottom: near infrared fluorescent dye-isocyanine green); Therapy (left: doxorubicin, center: paclitaxel, right: camptothecin).

Figure 2

Schematic diagrams of targeted nanoparticles that utilize local factors from the tumor microenvironment to improve drug delivery to tumors. (A) Carriers containing MMP-sensitive cell-penetrating peptides. A polycationic cell penetrating peptide is connected to a neutralizing polyanion via a matrix metalloproteinase (MMP)-cleavable linker. Dissociation of the polyanion, following MMP-mediated cleavage enables the activated cell penetrating peptide to associate with and enter cells. (B) pH-responsive glycol chitosan (GC)-nanoparticles. At physiologic pH, the surface amines on the GC-nanoparticles are deprotonated and carry a net neutral charge. Within the acidic tumor microenvironment, the GC-nanoparticles acquire a net positive surface charge and exhibit electrostatic interactions with negatively charged cell membranes, leading to enhanced tumor retention. (C) Action of pH low insertion peptide (pHLIP). pHLIP is a water-soluble membrane peptide that shows little to no interaction with cell membranes at physiologic pH, but at slightly acidic pH forms a stable transmembrane alpha-helix and inserts into the cell membrane. (D) pH-responsive nanoparticles. Nanoparticles shed their protective coating within an acidic tumor microenvironment, exposing an underlying positive surface charge that promotes electrostatic interactions with surrounding cells. This ‘unmasking’ process may also be triggered by other stimuli including reducing agents and proteases.