Focus on Fundamentals: Achieving Effective Nanoparticle Targeting

Abstract

Successful molecular targeting of nanoparticle drug carriers can enhance therapeutic specificity and reduce systemic toxicity. Typically, ligands specific for cognate receptors expressed on the intended target cell type are conjugated to the nanoparticle surface. This approach, often called active targeting, seems to imply that the conjugated ligand imbues the nanoparticle with homing capacity. However, ligand-receptor interactions are mediated by short-range forces and cannot produce magnetic-like attraction over larger distances. Successful targeting actually involves two key characteristics: contact of the nanoparticle with the intended target cell and subsequent ligand-mediated retention at the site. Here we propose a conceptual framework, based on recent literature combined with basic principles of molecular interactions, to guide rational design of nanoparticle targeting strategies.

Keywords: ex vivo organ perfusion; kinetic competition; nanoparticle; receptor–ligand binding; vascular targeting.

Copyright © 2018 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Key differences in receptor-ligand binding in vitro versus in in vivo nanoparticle targeting

The principles of receptor ligand binding are often determined in simplified in vitro experiments, where there is negligible interaction with the inert environment, and the concentrations of ligand and receptor can be controlled to ensure equilibrium conditions are met. By contrast, systemic ligand-mediated targeting is done in a competitive environment, where the concentration of available ligands is diminished over time due to non-specific binding and actions of the mononuclear phagocyte system. In this setting, it is unlikely that delivering ligands in excess of receptors can ever be accomplished regardless of non-specific elimination. Additionally, even though a known amount of ligand-nanoparticle (NP) can be administered, hemodynamic effects on nanoparticle distribution within a vessel and the heterogeneity of the target receptors mean that local concentrations cannot be exactly known. Finally, the accessibility of a target in vivo is highly variable depending on the target cell type location. These attributes together contribute to an inherently complex, non-equilibrium environment.

Key Figure 2. Applying the Law of Mass Action to optimize the two steps to in vivo ligand-mediated nanoparticle targeting

The first step to maximizing targeted nanoparticle (NP) retention is maximizing the frequency of NP-cell contact. In the Law of Mass action, which can be used to describe the rate of NP-cell binding, this term is represented with concentrations of the target cell (A) and the NP (B). Targeting highly accessible cells (e.g. the endothelium; Left panel) versus cells in the parenchyma, allows NPs to come within close range of the target where molecular interaction forces can act thereby allowing receptor-ligand binding to occur. Reducing NP elimination by the mononuclear phagocytotic system (MPS) slows the reduction of NP concentration over time also allowing for more frequent NP-cell contact (Middle panel). The second step is to design successful ligand engagement of the target cell. Choosing targets and designing NP systems with high density of ligands and receptors can contribute to fast on rates and slow off rates between ligand and receptor, which increases the likelihood that chance contact will result in retention of the NP and reduces the likelihood that the nanoparticle will be released form the cell surface prior to internalization.

Figure 3. Ex vivo organ perfusion as a setting for vascular-targeted nanoparticles

In this procedure, human organs (e.g. kidney, pictured above) are connected to a closed circulation loop, maintained by a mechanical centrifugal pump. Perfusates, such as washed and suspended red blood cells, are kept at or near normal body temperature. Supplying continuous flow supplemented with oxygen supply and necessary nutrients extends the time that an organ can retain healthy function outside of the body while awaiting transplant. The period of ex vivo perfusion provides privileged access to the organ, significantly limiting the complications and variables of systemic delivery systems. The isolated nature of the organ also simplifies measurement of nanoparticle delivery characteristics and physiological function to assess any impact of therapeutic delivery.