Our efforts are focused on designing new nanoparticle compositions that possess an alternative delivery mechanism whereby a hydrophobic to hydrophilic transition is triggered by a physiologic stimulus resulting in swelling and rapid release of their contents. The potential benefit of this approach is the intracellular release of the drug giving high local concentrations at the site of delivery with low systemic exposure. To develop such pH responsive expansile nanoparticles, we prepared crosslinked nanoparticles from a hydrophobic monomer in which the hydroxyl groups of the resulting polymer nanoparticles are masked by an acid-labile protecting group. At neutral pH the nanoparticles are stable and do not release the encapsulant. A decrease in pH cleaves the protecting group and reveals the hydroxyls, causing the desired hydrophobic to hydrophilic transformation.
As shown in the figure, nanoparticles were prepared using a miniemulsion polymerization technique, which combines high-energy emulsification and free radical photopolymerization of an acrylate monomer. Nanoparticles prepared from monomer 1 or 2 were exposed to buffered aqueous solutions of pH 5 or 7.4, and the diameter of the particles was measured at regular time intervals over 24 hours using DLS. Nanoparticles prepared from monomer 1 swelled at pH 5, but not at pH = 7.4 and hence are called expansile nanoparticles. In comparison, nanoparticles prepared from monomer 2 did not swell at either pH condition .
In order to assess the efficacy of paclitaxel-loaded expansile nanoparticles to prevent establishment of lung cancer in an in vivo model mimicking microscopic disease that can remain when the surgical margin is close to the tumor, we evaluated paclitaxel-loaded expansile nanoparticles in a rapidly growing subcutaneous tumor model. 750,000 LLC tumor cells plus paclitaxel-loaded expansile nanoparticles (2 or 20 μg Pax) were injected subcutaneously into the flank of a mouse. The contralateral flank received a second injection of 750,000 LLC cells alone or LLC cells mixed with an equivalent dose of empty expansile nanoparticles, paclitaxel-loaded non-expansile nanoparticles, or paclitaxel solubilized with Cremophor as used clinically. Animals were monitored clinically, and tumors were measured twice a week. As shown in the figure, large tumors were noted at the site where LLC cells were co-injected with media alone, empty expansile nanoparticles, paclitaxel-loaded non-expansile nanoparticles, or paclitaxel alone. In contrast, sites receiving LLC cells plus paclitaxel-loaded expansile nanoparticles showed a significantly reduced incidence of tumor and tumor burden. The results suggest that nanoparticles possessing the responsive expansile characteristic are an effective delivery vehicle for paclitaxel and superior to current delivery methods using Cremophor.