PEG Nanocages as Non-sheddable Stabilizers for Drug Nanocrystals

Many potent drugs are difficult to administer intravenously due to poor aqueous solubility. One validated approach for addressing this issue is to process them into colloidal dispersions known as "nanocrystals" (NCs). However, NCs possess high-energy surfaces that must be stabilized with surfactants to prevent aggregation. In addition, the stabilizer provides a means of anchoring targeting moieties to the NCs for achieving deposition or uptake at specified locations. Nevertheless, a critical challenge is that the surfactant (and consequently the targeting agents) can be shed upon high dilution. This work demonstrates successful cross-linking by click chemistry of stabilizers around paclitaxel NCs to form polymeric "nanocages". Cross-linking does not cause aggregation, as evidenced by transmission electron microscopy, and the nanocages retained the particulate drug through a combination of physical entrapment and physisorption. Size measurements by dynamic light scattering showed that nanocages act as sterically stabilizing barriers to particle-particle interactions and aggregation. The nanocages were shown to be less shed from the NCs than comparable non-cross-linked stabilizers. This contribution provides crucial general tools for preparing poorly sheddable stabilizing coatings to NCs and potentially other classes of nanoparticles for which covalent attachment of the stabilizer to the particle is undesirable (e.g., a drug) or impossible (chemically inert). The presented approach also offers the possibility of more stably attaching targeting moieties to the latter by use of heterotelechelic PEG derivatives, which may favor active targeting and internalization by cells.