Drug delivery: One nanoparticle, one kill

Abstract

By wrapping a ligand-functionalized lipid membrane around a silica core, nanoparticles with a fluid surface are created. These combine unprecedented specificity in binding to cancer cells with the combinatorial delivery of drug cocktails.

Figure 1

A schematic outlining multivalent targeting in nanoparticle drug delivery. Drug-loaded nanoparticles carrying therapeutics to tumour sites undergo a multistep process to achieve their therapeutic goal, beginning with extravasation from leaky tumour vessels (a), diffusion past non-target cells lacking receptors for the targeting ligand (b) and initial binding to receptors on target (for example, tumour) cells (c). Particles carrying low densities of targeting ligands on their surface are less likely to elicit an immune response or bind non-specifically to non-target cells. However, if low-density ligands are immobile on the two-dimensional surface of the particle, multivalent binding to the target cell may not be possible and the lifetime of binding to the target cell may be too short to achieve internalization (d). In contrast, when ligands can diffuse over the two-dimensional particle surface, initial binding to targets can be followed by cooperative engagement of additional receptors as ligands diffuse into the particle/cell interface (e). This can lead to near-irreversible binding and rapid particle internalization for drug delivery into the cell (f).

Figure 2

The design of lipid-bilayer-wrapped nanoporous silica, termed protocells. Nanoporous silica cores are loaded with multivariate drug cargos by adsorption to the silica matrix. The drug-loaded core is then enveloped by a single lipid bilayer, which is further functionalized with poly(ethylene glycol) (to reduce non-specific interactions with its environment), peptides (to direct binding to distinct target cells) and pH-responsive peptides, which cause disruption of endosomes and the bilayer coating on particle internalization into acidic intracellular compartments, allowing drug delivery into the cytosol of the target cell. Figure adapted from ref. 4.