Molecular and cellular sensors

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Research Synopsis

Our research efforts are directed towards developing and engineering new sensors and probes for the study of biological function and the detection and diagnosis of disease. The projects underway involve aspects of diverse disciplines ranging from biomolecular chemistry, molecular biology, and cell biology to materials science and nanotechnology.

Organelle-specific peptidoconjugates Eukaryotic cells are complex structures with specialized compartments – organelles - that play important functional roles. We have developed a class of peptide-based conjugates displaying organellar targeting within human cells that can be used to probe specific compartments and deliver agents with chemical or biological activity. Ongoing efforts involving these compounds will focus on the following issues: probing organelle-specific stress responses elucidating molecular requirements for organellar localization use of molecular-level information concerning cellular trafficking of peptide-based compounds for engineering pharmaceutical agents with increased efficacy

Images obtained by fluorescence microscopy of peptidoconjugates localized to the nucleoli and mitochondria of living cells

Nanoscale sensors for the detection of cancer biomarkers
Advances in genomic and proteomic methods now allow classification of disease based on molecular profiling. The detection of a molecular analytes and use of this type of information for disease diagnosis requires methods with superior sensitivity and specificity, along with high-throughput. We are developing new analytical methods with these properties that will permit the direct readout of nucleic acid sequences and protein biomarkers. Novel technologies for ultrasensitive nucleic acids sensing have been developed in our laboratories that use electrochemical methods for readout. Nanomaterials play an important role in this effort, as detection sensitivity is greatly enhanced when measurement are performed at the nanoscale. Our aim is to generate sensors applicable to the diagnosis of cancer and other pathologies.

Schematic illustration of a nanoscale nucleic
acids sensor developed by the Kelley group.

Biotemplated quantum dots
The worlds of biology and semiconductor engineering have traditionally been quite distinct. The spontaneous assembly of biological materials presents a stark contrast to the rational fabrication required for high performance semiconductors. The merger of these diverse materials represents a tremendous opportunity, given that biomolecules can organize into intricate, functionally sophisticated structures – exactly the sort of precise, elegant control urgently needed to make the next generation of materials for computing, communications, energy, and the environment. Thus, we are working towards using biomolecular templates – particularly nucleic-acids based scaffolds for the synthesis of semiconductor nanocrystals. We have demonstrated that rational programming of the size and luminescence spectra of colloidal quantum dot nanocrystals is possible through the choice of nucleotide ligands responsible for nanoparticle nucleation, growth, stabilization, and passivation. Moreover, we have shown that nucleic acid conformation can be used to modulate structures of nanocrystals. Recently, we demonstrated that tRNAs can be used as a scaffold and ligand system for CdS nanocrystals. The results obtained thus far point the way to programmable synthesis of nanoparticles using precisely-controlled polynucleotide sequences.

Transfer RNA-templated semiconductor
nanocrystals – a biotemplated nanomaterial

“Site-Specific Delivery of DNA and Appended Cargo to Arrayed Carbon Nanotubes.” B.J.Taft, A. Lazareck, J.M. Xu, and S.O. Kelley, J. Am. Chem. Soc., 2004, 126, 12270.

“Ultrasensitive Electrocatalytic DNA Detection with 3D Nanoelectrodes.” R.L. Gasparac, B.J. Taft. and S.O. Kelley, J. Am. Chem. Soc., 2004, 126, 12750.

“Synthesis, Characterization, and Cellular Uptake of Rose Bengal Peptidoconjugates.” J.R. Carreon, M.A. Roberts, L.M. Wittenhagen, and S.O. Kelley, Organic Letters, 2005, 7, 99.

“Phototoxicity of Peptidoconjugates Modulated by a Single Amino Acid.”
L.M. Wittenhagen, J.R. Carreon, E.G. Prestwich, S.O. Kelley,
Angew. Chem., 2005, 44, 2542.

““Programming Nanoparticle Growth using Nucleic Acid Ligands” S. Hinds, B.J. Taft, L. Levina, V. Sukhovatkin, M.D. Roy, C.J. Dooley, M.D. Roy, and E.H. Sargent, and S.O. Kelley, J. Am. Chem. Soc., 2006, 128, 64.

“RNA-Templated Semiconductor Nanocrystals.” N. Ma, C.J. Dooley, and S.O. Kelley, J. Am. Chem. Soc., 2006, 128, 12598.