A Multi-Scale Hybrid Nanoparticle Platform with Controlled Cellular Interaction and Targeting Kinetics

Polymeric nanoparticles (NPs) and dendrimers are two major classes of nanomaterials that have demonstrated great potential for targeted drug delivery. However, they each have drawbacks such as limited tissue diffusivity/tumor penetration and rapid in vivo elimination, respectively. To address these issues, as a proof-of-concept study, we designed hybrid NPs (nanohybrids) that combined a polycationic polymer, PEI, with protective outer layers of polylactide-co-glycolide (PLGA), polyethylene glycol-b-polylactide-co-glycolide (PEG-PLGA), or PEGylated liposomes. The nanohybrids demonstrated controlled cellular interactions and cytotoxicity kinetics by controlling the release of PEI. We then investigated the ability of the nanohybrid platform to control the targeting kinetics of actively-targeted dendrimer conjugates forming the core of the nanohybrids. Folate (FA)-targeted poly(amidoamine) dendrimers were encapsulated within poly(ethylene glycol)-b-poly(D,L-lactide) NPs. The nanohybrids (~100 nm NPs encapsulating ~5 nm targeted dendrimers) maintained high selectivity to FA receptor (FR)-overexpressing KB cells (KB FR+) resembling the selectivity of free dendrimers, while displaying controlled cellular interaction kinetics due to the presence of the polymeric NP shells. Simulated penetration assays using multicellular tumor spheroids of KB FR+ cells revealed that the targeted dendrimers penetrated deep into the spheroids upon their release from the nanohybrids, whereas the NP shell did not. Biodistribution studies in healthy and tumor-bearing mice showed that by encapsulating FA-targeted dendrimers within PEGylated NPs, the larger size of the nanohybrids and the controlled release of the dendrimer conjugates delayed their renal elimination. This allowed for more efficient tumor accumulation compared to free FA-targeted dendrimers through a combination of passive and active targeting. Our results provide evidence that selective cellular interactions can be kinetically controlled by the nanohybrid design, which integrates the unique characteristics of dendrimers (effective targeting and penetration) and polymeric NPs (controlled release, suitable size for passive targeting, and long circulation). This hybrid design strategy demonstrates great potential to enhance the targeting efficacy of the individual nanocarriers.