Targeted nanoparticle formulation for a poorly water soluble Gemcitabine derivative and its in vivo and in vitro anti-tumor activity

Cancer is a collection of over one hundred different types of diseases and is responsible for the leading cause of death in the United States. More strikingly, cancer mortality rates have remained relatively unchanged for the past several decades, indicating significant clinical demand for improved cancer therapy. Gemcitabine, known clinically as Gemzar®, is used to treat a variety of human cancers, however, clinical efficacy is modest due to it’s brief blood circulation, rapid clearance, manifestation of tumor-drug resistance, and lack of drug specificity. This thesis sought to develop a solid lipid nanoparticle-based platform to passively and actively target a gemcitabine lipophilic derivative, 4-(N)-stearoyl gemcitabine, into tumor cells over-expressing epidermal growth factor receptor (EGFR) after intravenous injection. Considering gemcitabine is hydrophilic and the core of the nanoparticle is solid (hydrophobic), we lipophilized gemcitabine by conjugating a stearoyl group to its N-terminus to form 4-(N)-stearoyl gemcitabine. Second, we incorporated stearoyl gemcitabine into lecithin-based nanoparticles. The nanoparticle formulation was prepared from lecithin/glyceryl monostearate-in-water emulsions. Third, we grafted the gemcitabine nanoparticles with polyethylene glycol chains with reactive end groups that are capable of conjugating with a targeting moiety on the surface to actively target tumors that over-express EGFR. Taken together, the overall objective of the research presented in this thesis is to develop, characterize, and evaluate the anti-tumor performance in vitro as well as in mice against both human and mouse tumor models.