Polymeric PRINT Hydrogel Nanoparticles: Next Generation Drug Delivery Vehicles Targeting Cancerous Tissue

Standard cancer treatment generally consists of surgery, radiation, and small molecule chemotherapies that distribute systemically throughout the body. The systemic distribution of a toxic chemotherapeutic commonly produces unwanted side-effects leading to dose-limiting toxicity (such as fatigue, hair loss, anemia, nausea, nerve damage, and in some cases death). Accompanying the large volume of distribution (Vd) and subsequent dose-limiting toxicity, small molecule therapies may display less than desirable pharmacokinetic behavior due to poor solubility and low permeability once administered orally or intravenously. Over the last 30 years of development, the use of nanoparticulate drug carriers has resulted in lowered Vd, enhanced solubility and permeability of the cargo, and improved efficacy in both academic and clinical endeavors. In addition, the increased size of a carrier, in comparison to the drug cargo, has been observed to enhance permeation and retention into the porous tumor vasculature. However, while manufacturing these nano-carriers, issues arise due to intrinsic particle heterogeneity associated with common fabrication methods. The use of Particle Replication in Non-wetting Templates (PRINT®) technology helps overcome this issue and allows for fine control over shape, size, modulus, composition, and surface chemistry. In this account, PRINT is employed to fabricate nanoparticle carriers that exhibit precisely engineered surface characteristics and size that are optimal for tumor deposition. The surface of PRINT hydrogels were precisely functionalized with a coating of poly (ethylene glycol), or PEG, that elicited inhibition of protein binding, macrophage resistance, and a vastly improved blood circulation half-life compared to non-PEGylated counterparts upon administration in vivo. Upon attachment of an EGFR targeting affibody to the terminal end of this PEG group, dramatic changes were observed in vitro and in vivo with changes in density of targeting ligand. In addition, a number of different murine cancer models were analyzed for passive particle tumor accumulation revealing size and disease model dependent neoplastic sequestration, as well as, preferential accumulation in primary and metastatic disease sites. Finally, preliminary experimentation with environment-sensitive pro-drug linkages revealed site-specific cargo release in dissolution studies. Overall, these efforts may lead to improved drug delivery to cancerous tissue and aid in the development of next generation drug delivery vehicles.Doctor of Philosoph