Mark E. Davis - US grants

Dr Mark Davis is receiving the Alan T. Waterman Award for his pioneering work in catalysis and catalytic materials, including the first synthesis of a molecular sieve with pores larger than one nanometer and the invention of supported aqueous-phase catalysts; each of these accomplishments opens up a new and potentially important area in catalytic science and technology, and also has implications for separations technology and environmental control.

ABSTRACT CTS-9422458 Mark Davis A workshop is organized and conducted to define standard reference materials and properties for zeolites. A formal proposal to the National Institute of Standards and Technology for establishment of these standards is prepared. Zeolites are widely used for several important industrial processes. They serve as detergents, separation agents, and catalysts. However, widely accepted standards are lacking, making definition of quality difficult.

CTS-9504901 Gavalas Cal Tech The fundamentals of in-situ formation of zeolite films on porous substrates will be studied in order to synthesize membranes of high permeance and selectivity. Films of ZSM-5 and zeolite A will be grown on porous alumina plates or tubes placed in clear solutions of suitable compositions maintained at appropriate temperature and autogeneous pressure. Control of crystal size, film quality and thickness will be achieved by varying the pore size of the substrate and synthesis conditions. Characterization and permeation experimelts will be performed to evaluate the performance of the membrane in important gas separations. The research may lead to the development of improved zeolite membranes with potential applications in separations, catalysis and reaction engineering.

9724240 Davis Nuclear magnetic resonance (NMR) equipment will be acquired by the California Institute of Technology. The equipment includes 200 MHz, 300 MHz, and 400 MHz NMR spectrometers. The instruments will support research projects in materials chemistry and materials physics, including synthetic and catalytic studies of molecular sieves, order and dynamics in polymers, and the development of high sensitivity NMR methods. %%% The instrumentation will be part of a unique multi-user, solid state NMR facility, accessible to users within the Los Angeles basin. Students will be trained in the technique and in the use of the instruments, both through individual sessions and through a formal course. ***

On June 19-20, 2003, a leading group of engineers and scientists from academia and industry will meet at the National Science Foundation for a visionary workshop on future directions in catalysis research. Catalysts and the multitude of products prepared through their use constitute a major portion of the US GNP. Undoubtedly, catalysts are the most successful application of nanotechnology in the modern economy. The ability to design and control catalyst structure at the nanometer scale is directly related to key catalytic properties, such as activity, selectivity, and stability. Recent advances now promise to revolutionize catalysis research: Synthetic techniques can now control assembly at the nano-scale, analytical methodologies can identify and probe structure to verify synthesis methodology, and predictive capabilities can provide guiding principles for structure/property relationships. Unprecedented control of the preparation of new nano-scale catalysts is on the near horizon.

This workshop will also address the role of catalysis within the framework of national inititatives in nanoscience and engineering. NSF's Mihail Roco, chair of the U.S. National Science and Technology Council's Subcommittee on Nanoscale Science, Engineering, and Technology (NSET), will present an overview of U.S. government efforts in nanotechnology research and development. Professor Mark E. Davis of the California Institute of Technology, who received the Alan T. Waterman Award, from the National Science Foundation in 1990, will present the charge and goals for the workshop. Plenary talks will be given on seven key topics explored by the workshop:

- Professor Don Tilley, University of California-Berkeley - Molecular Precursors to Catalytic Materials

- Professor Chad Mirkin, Northwestern University - Perspective on the Relationationship to Other Nanoscience and Engineering Programs

- Dr. E. Mark Davis, ExxonMobil - Perspective on Catalysis and Assembly at the Nanoscale by Industry

- Professor Robert Schlogl, Fritz Haber Institute, Berlin - Perspective On Heterogeneous Catalysis at the Nanoscale from Europe

- Professor Henry Foley, Pennsylvania State University - Use of Catalysis for Nanoscale Materials Fabrication

- Professor Raul Lobo, University of Delaware - Characterization Methods for Nanoscale Catalysts

- Professor Matt Neurock, University of Virginia - Computation and Modeling for Nanoscale Catalysis

Workshop participants will discuss these topics and develop a visionary plan for future NSF research in this aspect of catalysis. The results of the workshop will be released in a report following the meeting, and a web site will be developed.

04369895
Davis

This three-year U.S.-France cooperative research project between Mark E. Davis of the California Institute of Technology and Veronique Dufaud of the Laboratoire de Chimie, Ecole Normale Superieure in Lyon, France focuses on preparing solid catalysts of structural uniformity. The proposed project is an extension of the U.S. and French investigators previous work on synthesis and catalytic behavior of mesoporous silicas containing positioned sulfonic acid groups.

Intellectual Merit

The objective is to investigate structure-property relationships of organic-inorganic hybrid materials where the inorganic component provides surface area and porosity and the organic groups are organized on its surface. Results from zeolite-based catalysts suggest strong correlation between nanoscopic/mesoscopic uniformity and high selectivity. The investigators propose to create structural uniformity that contains: (1) multiple organic groups in precise arrangement in order to study the effects of cooperativity; and (2) multiple organic group types to catalyze multistep reaction pathways.

Broader Impacts

The proposal adds an international dimension to an active NSF - NIRT (Nanoscale Science and Engineering Independent Research Team) research award on zeolite nanoparticles. The U.S. investigator is expert in synthesis and characterization of organic-inorganic hybrid materials and has broader experience in catalysis. This is complemented by French expertise in synthesis and surface organo metallic chemistry. Their efforts will advance understanding and creation of new catalysts. Catalytic activity is the basis for the chemistry industry. The project gives a U.S. postdoctoral research and graduate student an international experience via research immersion at a leading French institution. The project advances the student's international research skills and assists with developing international connections for future.

DESCRIPTION (provided by applicant): Non-viral (synthetic) nucleic acid delivery systems have the potential to provide for the practical application of nucleic acid-based therapeutics. We have designed and created a tunable, self-assembling, non-viral nucleic acid delivery system that is based on cyclodextrin-containing polymers (CDP) and this delivery system has been shown to have very low toxicity in animals and give gene expression in targeted tissues from an intravenous administration. We propose to evaluate the hypothesis that our properly designed and engineered, synthetic, non-viral delivery vehicle bearing galactose-based targeting moieties can effectively deliver nucleic acids to hepatocytes in mice if the particle diameters do not exceed 70 nm and the surface charges are in the range of +/-10 mV. Specific Aims: 1. Formulate siRNA-containing, CDP-based particles with galactose-based targeting ligands of ca. 70 nm diameter or less with surface charges within the range of +/-10mV that can be recognized and processed by the asialoglycoprotein receptor on hepatocytes and determine the optimal physicochemical properties for maximum downregulation time and efficiency of a hepatic gene following systemic administration to mice. 2. Formulate plasmid DNA (pDNA)-containing, CDP-based particles using the conclusions obtained in Specific Aim 1 to guide the assembly and administration protocols and determine the gene delivery efficiency and the time course of gene expression in hepatocytes of mice using both marker and therapeutic genes. Significance: The development of effective, synthetic delivery vehicles for targeting hepatocytes would provide a generalized methodology for treating numerous diseases. Long-term goals: The potential for providing new disease treatments using nucleic acid-based therapies, the so-called gene therapies, has been restricted by limitations in the safe and effective delivery of nucleic acids. The long-term objective of our proposal is to design and engineer a generalized, synthetic system for ultimately delivering nucleic acid-based therapeutics to hepatocytes in humans.

DESCRIPTION (provided by applicant): A Novel Method of Nanoparticle Delivery to Brain by Targeting Ec-gp96 ABSTRACT The blood brain barrier (BBB) is composed of brain microvascular endothelial cells connected each other with tight junction molecules thereby, making the barrier impermeable to toxins, bacteria, viruses, and other unwanted substance from blood. This specific characteristic feature of the BBB along with efflux pumps prevents the delivery of therapeutic compound to treat brain diseases. Although, several methods have been identified to target the central nervous system for drug delivery, non-specificity is a major problem with these strategies. One of the critical challenges in drug development is the delivery of drugs to the central nervous system (CNS) across the BBB. E. coli studies by Nemani group, performed using both an in vitro model of human brain microvascular endothelial cells and in newborn mice, have been used to identified a BBB specific receptor, Ec-gp96 to which E. coli K1, a meningitis causing bacterium binds and enters the brain. This interaction occurs between outer membrane protein A of E. coli and Ec-gp96 for binding to and entry of the BBB. The computer modeling studies of OmpA-Ec-gp96 interaction by Goddard group have predicted several compounds compatible with the binding to Ec-gp96. Of these several have been shown to be effective in preventing the binding of OmpA of E. coli with Ec-gp6 and thus inhibiting the invasion of the bacteria in HBMEC. This has identified for the first time small molecule ligands for Ec-gp96. Furthermore, Davis group has developed CDP nanoparticles to deliver drugs or other payloads to treat cancers and some of the methods are being tested in Phase I and Phase II clinical trials. These exciting experimental results set the stage for this proposal which will design Ec-gp96 targeting ligands and conjugate them to nanoparticles to develop a delivery system specifically targeting the blood-brain barrier. PUBLIC HEALTH RELEVANCE: This proposal is aimed at designing ligands targeting a protein only found in the cells lining the blood-brain barrier, that will be used to make a drug-delivery system based on nanoparticles to specifically deliver drugs into the brain.

Rapid translation from validated molecular targets in cancer to treatments that benefit patients has been hampered by difficulties in rapidly developing effective, targeted therapeutics, as many targets are not druggable by traditional medicinal chemistry approaches. We propose here to invesfigate a new methodology to accelerate the translation of understandings of molecular events in cancer cell biology into new therapies by using RNA interference-based therapeutics (targeted nanoparticle based systems are used here) combined with multi-time point blood/serum-based miRNA profiling. This strategy will be demonstrated using a previously undruggable target, the oncogenic N-Ras mutation in melanoma. We propose to evaluate the hypothesis that the integration of targeted delivery of RNA interference-based therapeutics that allow quick translation from concept to clinic with multi-time point blood/serum monitoring of cancer-specific miRNA biomarkers can rapidly lead to mechanistically verified cancer treatments with blood/serum biomarkers that can provide minimally invasive proof of function in patients. Specific Aims: 1. Demonstrate tumor targeting, N-Ras knock-down, and anti-tumor effects with systemically delivered nanoparticles carrying siRNA. 2. Demonstrate that minimally invasive, multi-time point blood/serum miRNA measurements correlate with multi-time point miRNA profiles in tumors after initiation of RNAi that inhibits the N-Ras gene product. 3. Demonstrate that systemically delivered nanoparticles carrying anti-N-Ras siRNA can provide antitumor effects and that the time course of the N-Ras gene inhibition can be monitored via blood/serum miRNA profiles

DESCRIPTION (provided by applicant): Escherichia coli K1 is the most common cause of meningitis in neonates. Ineffectiveness of antibiotic therapy over the last few decades and the emergence of antibiotic resistant E. coli strains imply that there is a great unmet need for new methods of treatment and prevention. Incomplete understanding of the mechanisms involved at every step of pathogenesis is attributed to this poor outcome. For example, the mechanisms by which E. coli K1 enters the human brain microvascular endothelial cells (HBMEC) that constitute the BBB and disrupts tight junctions (TJs) are poorly understood. We have established that outer membrane protein A (OmpA) of E. coli interacts with endothelial cell gp96 (Ecgp); a receptor specifically expressed on HBMEC, to invade and disrupt the TJs. The importance of OmpA-Ecgp interaction is further supported by our findings that 1) E. coli strains that either lack OmpA or express non-functional OmpA do not induce meningitis in a newborn mouse or rat model and 2) Mice in which Ecgp expression was suppressed were resistant to E. coli infection. Intriguingly, OmpA interaction with Ecgp triggers the production of nitric oxide (NO) due to iNOS activation and thereby enhances the expression of the receptor to allow the bacteria to invade more efficiently. In agreement, iNOS-/- mice are resistant to E. coli infection and also administration of an iNOS specific inhibitor, aminoguanidine (AG), during high-grade bacteremia prevented the occurrence of meningitis. Novel computer modeling methods were utilized to study the interaction of OmpA and Ecgp and to identify small molecule inhibitors that prevent the E. coli invasion of HBMEC. Three small molecules exhibited more than 80% inhibition of E. coli invasion in HBMEC both in vitro and in vivo. Our studies have also revealed that Ecgp interaction with Robo4 at the HBMEC membrane increases upon infection with E. coli. Further, a GTPase activating protein, IQGAP1, which binds both actin and b-catenin, appears to play a role in the invasion process. IQGAP1 is a client protein for Stat3, which was shown to be associated with Ecgp, indicating that IQGAP1 might be relaying Ecgp mediated signals to induce E. coli invasion. Thus, our hypothesis is that the interaction of OmpA and Ecgp is fundamental to initiate signaling events that induce E. coli invasion and increased permeability of the BBB. In Aim 1, we propose to define the binding domains of Ecgp that orchestrate the interaction of Ecgp/Robo4 with OmpA. Next, to understand whether Ecgp interaction with Robo4 contributes to signaling events to induce NO production and thereby modulating IQGAP1 association with b-CAT to dislodge it from TJs will be tested in Aim 2. Then, in Aim 3 we will modify the antagonists for higher inhibition efficiency and couple them to nanoparticles, which will carry a load of iNOS inhibitors to deliver to brain to prevent E. coli induced meningitis in newborn rats. Translational medicine is the outcome of this application in which studies of basic biology and applied technology to develop new strategies of prevention will be integrated.

PROJECT 1: Targeted Nanoparticle Therapeutics for Treating Intracranial Disease. ABSTRACT: Patients with primary brain cancers and brain metastases from other cancers are difficult to treat, as most systemically administered therapeutic agents do not reach intracranial disease. The blood-brain barrier (BBB) limits many small molecule drugs and essentially all macromolecular therapeutic agents (peptides, proteins, nucleic acids) from reaching the brain. While some intracranial tumors can eventually breach the BBB, this project focuses on reaching disease that is accessible via an intact BBB. We propose to create a targeted nanoparticle (NP) that crosses an intact BBB to deliver therapeutic agents to intracranial tumors in mouse models of the human disease. Here, we will initiate our investigations using mouse models of glioblastoma (GBM). The Davis group has translated two different NPs into clinical studies for a variety of cancers (CRLX101[1] ? contains a small molecule drug, and CALAA-01 [2,3]- contains siRNA). The NP CALAA-01 utilizes transferrin for surface receptor targeting agent and siRNA as the therapeutic entity. Recently, Davis' group showed how transferrin-containing NPs can cross an intact BBB in mice if the NP properties are properly designed [4]. Here, we will exploit those findings to create targeted NPs that can transport single or multiple therapeutic agents (the central NSBCC theme) across the BBB and into GBM tumors from systemic administrations in mice. Successful completion of this project will provide therapeutic modalities to address intracranial disease. Because sub-100 nm NPs will be the delivery vehicles, inclusion of multiple therapeutic entities (informed via the results that emerge from Project 4) within the NPs will allow combination strategies to be employed. Although work will begin with delivery of a single small molecule drug, success will enable combinations of multiple small molecule drugs, and extensions to individual and combinations of macromolecular therapeutic agents.