Biomedical Applications of Expanded Porphyrins

This is a year -30 renewal request that addresses a major challenge in medicinal chemistry, namely reducing the systemic toxicity of chemotherapeutics. In prior work, we showed that conjugation of a Pt(IV) center to a water solubilized texaphyrin core called motexfin gadolinium (MGd) allowed for near-complete tumor regrowth suppression in a patient-derived xenograft ovarian cancer mouse model. We now propose to build on this success by creating metallotexaphyrin conjugates bearing poly (ADP-ribose) polymerase 1 (PARP) inhibitors and Au(I) payloads. Advantage will be taken of the fact that the properties of metallotexaphyrins vary with the metal. This, we suggest, will allow us to create tumor-targeting systems with functional features that include an ability to act as so-called PARASHIFT and 19-F nuclear magnetic resonance (NMR) probes, as well as promoting photo-induced thermal and pyroptosis effects. The net result should be systems that not only allow for imaging, but also give rise to therapeutic benefits that are enhanced relative to the active payload alone. To test this hypothesis, we will pursue the following specific aims: 1. Explore paramagnetic water solubilized lanthanide texaphyrins as a new class of potential PARASHIFT probes. Prepare new paramagnetic water soluble texaphyrin complexes and confirm that these complexes produce large downfield or upfield paramagnetic shifts of key 1-H signals (e.g., methyl resonances). Extend these studies to include fluorinated derivatives to allow concurrent 1H- and 19F-NMR based signaling. 2. Prepare and study In vitro texaphyrin conjugates based on PARP inhibitors and Au(I) centers. Synthesize texaphyrin conjugates based on PARP inhibitors and Au(I) centers. Study in platinum sensitive/resistant ovarian, BRCA1 normal/mutated triple negative breast and lung cancer cell lines. Test whether improvements are seen with easier-to-cleave linkers. 3. Test whether cell killing synergies with the conjugated payload are seen under conditions of red- light photo-irradiation in vitro. Test whether damage associated molecular patterns characteristic of pyroptosis or the increases in temperature expected for photothermal effects are seen for key texaphyrin conjugates upon photo-irradiation. 4. Carry the most promising systems on into in vivo studies using murine models. Treat tumor bearing mice with most promising conjugates for desired application i.e., MR imaging, photothermal and pyroptosis. Test acute toxicity, tumor growth inhibition and biodistribution.