Biological Activity of Rhodium Metalloinsertors and the Design of Bifunctional Conjugates

The Barton laboratory has established that octahedral rhodium complexes bearing the sterically expansive 5,6-chrysene diimine ligand can target thermodynamically destabilized sites, such as base pair mismatches, in DNA with high affinity and selectivity. These complexes approach DNA from the minor groove, ejecting the mismatched base pairs from the duplex in a binding mode termed metalloinsertion. In recent years, we have shown that these metalloinsertor complexes also exhibit cytotoxicity preferentially in cancer cells that are deficient in the mismatch repair (MMR) machinery.

Here, we establish that a sensitive structure-activity relationship exists for rhodium metalloinsertors. We studied the relationship between the chemical structures of metalloinsertors and their effect on biological activity for ten complexes with similar DNA binding affinities, but wide variation in their lipophilicity. Drastic differences were observed in the selectivities of the complexes for MMR-deficient cells. Compounds with hydrophilic ligands were highly selective, exhibiting preferential cytotoxicity in MMR-deficient cells at low concentrations and short incubation periods, whereas complexes with lipophilic ligands displayed poor cell-selectivity. It was discovered that all of the complexes localized to the nucleus in concentrations sufficient for mismatch binding; however, highly lipophilic complexes also exhibited high mitochondrial uptake. Significantly, these results support the notion that mitochondrial DNA is not the desired target for our metalloinsertor complexes; instead, selectivity stems from targeting mismatches in genomic DNA.

We have also explored the potential for metalloinsertors to be developed into more complex structures with multiple functionalities that could either enhance their overall potency or impart mismatch selectivity onto other therapeutic cargo. We have constructed a family of bifunctional metalloinsertor conjugates incorporating cis-platinum, each unique in its chemical structure, DNA binding interactions, and biological activity. The study of these complexes in MMR-deficient cells has established that the cell-selective biological activity of rhodium metalloinsertors proceeds through a critical cellular pathway leading to necrosis.

We further explored the underlying mechanisms surrounding the biological response to mismatch recognition by metalloinsertors in the genome. Immunofluorescence assays of MMR-deficient and MMR-proficient cells revealed that a critical biomarker for DNA damage, phosphorylation of histone H2AX (γH2AX) rapidly accumulates in response to metalloinsertor treatment, signifying the induction of double strand breaks in the genome. Significantly, we have discovered that our metalloinsertor complexes selectively inhibit transcription in MMR-deficient cells, which may be a crucial checkpoint in the eventual breakdown of the cell via necrosis. Additionally, preliminary in vivo studies have revealed the capability of these compounds to traverse the complex environments of multicellular organisms and accumulate in MMR-deficient tumors. Our ever-increasing understanding of metalloinsertors, as well as the development of new generations of complexes both monofunctional and bifunctional, enables their continued progress into the clinic as promising new chemotherapeutic agents.

Photonic and Device Design Principles for Ultrahigh-Efficiency (>50%), Spectrum-Splitting Photovoltaics

The sun has the potential to power the Earth's total energy needs, but electricity from solar power still constitutes an extremely small fraction of our power generation because of its high cost relative to traditional energy sources. Therefore, the cost of solar must be reduced to realize a more sustainable future. This can be achieved by significantly increasing the efficiency of modules that convert solar radiation to electricity. In this thesis, we consider several strategies to improve the device and photonic design of solar modules to achieve record, ultrahigh (> 50%) solar module efficiencies. First, we investigate the potential of a new passivation treatment, trioctylphosphine sulfide, to increase the performance of small GaAs solar cells for cheaper and more durable modules. We show that small cells (mm2), which currently have a significant efficiency decrease (~ 5%) compared to larger cells (cm2) because small cells have a higher fraction of recombination-active surface from the sidewalls, can achieve significantly higher efficiencies with effective passivation of the sidewalls. We experimentally validate the passivation qualities of treatment by trioctylphosphine sulfide (TOP:S) through four independent studies and show that this facile treatment can enable efficient small devices. Then, we discuss our efforts toward the design and prototyping of a spectrum-splitting module that employs optical elements to divide the incident spectrum into different color bands, which allows for higher efficiencies than traditional methods. We present a design, the polyhedral specular reflector, that has the potential for > 50% module efficiencies even with realistic losses from combined optics, cell, and electrical models. Prototyping efforts of one of these designs using glass concentrators yields an optical module whose combined spectrum-splitting and concentration should correspond to a record module efficiency of 42%. Finally, we consider how the manipulation of radiatively emitted photons from subcells in multijunction architectures can be used to achieve even higher efficiencies than previously thought, inspiring both optimization of incident and radiatively emitted photons for future high efficiency designs. In this thesis work, we explore novel device and photonic designs that represent a significant departure from current solar cell manufacturing techniques and ultimately show the potential for much higher solar cell efficiencies.