Targeted Cancer Therapy Systems: An In Silico Study of Radiohalogenated Ligands in the Estrogen Receptor and the Synthesis of a Molecular Toolkit for the Fabrication of Customizable Nanoparticles

Chemotherapy is often limited by off-target toxicity and the development of multi-drug resistance in response to treatment. Strategies which reduce off-target toxicity by passively or actively targeting cancer cells may improve the efficacy of chemotherapy. Herein, two projects relating to targeted therapy are described. In the first project, the binding modes of 1,1-bis(4-hydroxyphenyl)-2-phenylethylenes (THPEs), a class of synthetic estrogens previously developed by our group, in the human estrogen receptor alpha-ligand binding domain were studied using molecular modeling programs YASARA AutoDock and Schrodinger Glide. The results were internally consistent and supported the observation that a bromine or iodine atom at the 2-position of the THPEs contributes positively to their binding in the estrogen receptor. In the second project, a "molecular toolkit" approach to the synthesis of multifunctional nanoparticles was envisioned. Our hypothesis was that the physical and chemical properties of the final product could be defined by controlling the types and relative amounts of prefunctionalized polymer units (PPUs) as well as the emulsification conditions. The design and syntheses of heterobifunctional linkers and other components for a preliminary molecular toolkit are reported, and the literature on select heterobifunctional aliphatic linkers is examined.