Formulation and Development of Clinically Relevant Drugs

This dissertation makes contributions to the fields of anticancer drug formulation, synthesis and applications of nanoparticle adjuvants, and structure-activity relationships in drug discovery. Many drugs that are promising clinical candidates are potent in vitro, however their solubility and pharmacokinetic properties are suboptimal. Here we used various nano-formulations, primarily mesoporous silica nanoparticles, to improve the solubility and release properties of these drugs. In vivo results show that these nanoparticles are safe, multifunctional carriers that can be used for clinical imaging using positron emission tomography. In the second part of this work, porous aluminum oxide nanoparticles were synthesized for applications as immunological adjuvants, and polymer-coated mesoporous silica nanoparticles were used to deliver cyclic dinucleotides to stimulate the innate immune response. Lastly, UV-Vis spectroscopic assays were developed and used to understand how electronic properties of iron-binding heterocyclic thiosemicarbazone analogs are related to their inhibition of ribonucleotide reductase, an important target for cancer therapy. The structure-activity relationships that were discovered led to a promising drug scaffold for the treatment of cancers sensitive to nucleotide deprivation