Cancer has become one of the biggest threats to human health. In most cases, cancer cells can be differentiated from normal tissues via the overexpression of certain cellular membrane proteins. Improved therapeutic effects can be achieved by targeting these specific receptors. Compared to antibody targeting, small molecule targeting strategies have the advantages of efficient diffusion and delivery of theranostic agents into tumor tissue. This dissertation focuses on developing novel active targeting small molecule agents for cancer diagnosis and therapy. The focus of the first study is unique small molecules that bind the TrkC receptor, which is overexpressed in metastatic breast cancer (as well as gliobastoma, neuroblastoma, and melanoma). A conjugate of a TrkC ligand and the highly cytotoxic alkaloid, maytansinoid, was prepared. Cellular studies featuring TrkC+ and TrkC? human breast cancer cells indicated this conjugate might have a better therapeutic effect than the maytansinoid alone. It emerged that the conjugate was very efficacious in vivo, completely ablating orthotopic 4T1 breast tumor in one case, and dramatically reducing the tumor size in four other mice. The second study is based on a small sub-set of heptamethine (Cy7) dyes that are preferentially uptaken into tumors, then, in some cases, retained there for extended periods. These dyes absorb in the near infrared (NIR) region (above 750 nm), and deliver cargoes to various tumor models in vivo, offering theranostic effect. This study describes how four heptamethines were synthesized, all having the gemcitabine fragment attached to the meso-position of the Cy7 core. One theranostic agent localized in glioblastoma tumor cells with absorption maxima in NIR region and showed similar therapeutic effect to gemcitabine, but at one-third the molar dose. The third study describes work aimed at discovering a novel targeted small molecule from a one-bead one-compound (OBOC) combinatorial library. Two different screening protocols were established, and the on-bead compounds were effectively decoded with an extended linker and step-wise partial capping strategy. Some other efforts related to developing novel theranostic agents by targeting cancer cell surface receptors are also recorded. These either did not yield promising results or are a small part of much larger studies in our group.
