By Jason Bugno
Polymeric nanoparticles (NPs) have been heavily investigated as potential drug delivery tools for a few decades now, yet only a few have found their way into clinical trials. In light of this, many researchers have taken a step back to reevaluate their progress and look at what really matters when designing NPs for drug delivery. For instance, recently published works, such as this review by Wilhelm et al., have highlighted the importance of understanding the fundamental mechanisms governing how NPs interact with biological systems. Taking a closer look at how NP structure, chemistry, size, shape, and other physical properties dictate their interactions with tissues, cells, and biological components has provided a more detailed picture of these complicated processes. These new insights give us glimpses into how to better design NPs, focusing on how their physicochemical characteristics and biological interactions ultimately impact the capability to precisely deliver drugs to the intended targets.
When targeting drugs to solid tumors, it is critical to have NPs with finely tuned biodistributions. First off, the carrier needs to be stable in circulation and accumulate at the target site. Secondly, it needs to be able to permeate the tumor, distributing efficiently throughout the tumor. Looking deeper into the latter, my work has focused on understanding how ultrasmall NPs, less than 10 nm in size, interact with and penetrate solid tumors. Even small adjustments to their precise size and surface charge can drastically change NP-tumor interactions, greatly effecting both their accumulation within and penetration throughout a solid tumor model, known as multicellular tumor spheroids. I intend to use these findings to provide insights into how to design NPs based on their interactions with solid tumors.
The AAPS Foundation Graduate Student Fellowship has allowed me to more deeply investigate the mechanisms underlying how the size and surface charge contribute to the penetration, uptake, and transit throughout the spheroids. We have found that whereas smaller sizes (<3 nm) can rapidly penetrate to the spheroid core, their slightly larger counterparts (>5 nm) are retained more in the peripheral cells. Moreover, when the surface of the particles is positive, they exhibit significantly enhanced spheroid accumulation compared to neutral or negatively charged particles. Our findings provide design cues that can be used to engineer NPs for highly tailored tumor distributions, allowing one to target cells located on either the tumor periphery or deep within the core, through simple changes of the NP physical properties. By understanding the basics of how these NPs interact with the tumor, we are able to rationally construct them to provide highly tailored distributions and give them a better chance at making it to clinic.