A new and improved drug delivery system for targeting cancer - Ligand-targeted therapeutics is a rapidly growing class of anticancer agents. This class of therapeutics
is typically bifunctional molecules that use a targeting moiety to selectively deliver potent, typically
nonspecific, cytotoxic agents to cancer cells while sparing normal cells. The low-molecular-weight of
ligand-targeted therapeutics allows for better tumor penetration, especially in the case of solid tumors
where the size of antibodies is a limiting factor for effective treatment. Unfortunately, the poor
pharmacokinetic (PK) profiles of many of these conjugates present a challenge which limits their
tremendous therapeutic potential. Dose-limiting toxicity is also observed due to the need for high doses
and frequent administration. The overall goal of this proposal is to develop a fundamentally new
approach for reducing the toxicity and enhancing the PK properties of ligand-targeted therapeutics. The
main hypothesis of this proposal is to test whether conjugation of ligand-targeted therapeutics to a
selective ligand for the serum protein, transthyretin (TTR) (forming trifunctional molecules; TFMs) would
allow the TFMs to reversibly bind to TTR in serum. Binding of TFMs to TTR would enhance the in vivo
half-life of ligand-targeted therapeutics, and would also reduce toxicity by limiting their non-selective
tissue distribution. Here we propose to develop TFMs that bind selectively to prostate cancer (PCa)
cells that overexpress the prostate-specific membrane antigen (PSMA). PSMA is largely absent from
healthy tissues but highly expressed on the surface of PCa cells and on the new blood vessels that
supply nutrients to many other types of cancers. We have already made significant progress by
designing, synthesizing, and testing three TFMs (TFM1, TFM2, and TFM3) and our preliminary in vitro
and in vivo results are consistent with our hypothesis. In this proposal, we will continue evaluating
TFM1-3 in PCa cell culture and in vivo (PK in rats and efficacy/toxicity in mouse tumor xenograft
model). We will also synthesize additional series of TFMs. This should allow us to determine the
optimal linker system and affinity of TFMs to TTR and PSMA that will provide best balance between
enhanced PK, efficacy, and lower toxicity. Our proposed strategy is not limited to a particular disease
and the therapeutic action of TFMs could be determined by simply switching the payload or the
targeting agent. Therefore, we believe that a successful realization of our proposed studies has the
potential to significantly improve the therapeutic outcome and lower toxicity for patients suffering from
cancer and other diseases.
