Samuel Thomas, Ph.D. - US grants

TECHNICAL SUMMARY

Current limitations in the preparation and utilization of photoresponsive moieties have inhibited the development of enabling technologies that use the advantages of light-responsive polymers in new ways. The research objective of this award is to develop polymeric materials that have new photoresponsive properties because of the inclusion of photolabile groups, such as the o-nitrobenzylester (NBE) moiety. The central hypothesis of this research is that rational design of polymers with photolabile groups will enable photochemical control over the non-covalent intermolecular forces governed by hydrophobicity and charge-charge interactions. This research will focus on three classes of new light-responsive polymeric systems: 1) new block copolymers designed to switch from hydrophobic to hydrophilic, 2) layer-by-layer (LbL) polyelectrolyte films that switch interlayer electrostatic forces from attractive to repulsive, and 3) surface-bound polymeric coatings that switch the sign of the zeta potential. The proposed work is significant because it combines polymer synthesis and photochemistry to control intermolecular forces, resulting in new approaches to control matter with light. Expected outcomes of this research include polymers that photo-assemble into and disassemble from micelles, LbL films that are photopatternable in three dimensions, and coatings that enable photochemical control over electroosmotic fluid flow and static charging. These outcomes have potential applications in: 1) photochemically-labile carriers for targeted delivery, 2) all-aqueous photolithography, 3) photo-controlled microfluidic devices, and 4) photochemical control over the static charging of insulators.

NON-TECHNICAL SUMMARY

Materials that respond to light have major technological importance, with applications ranging from human health (e.g. imaging agents and photochemical delivery of therapeutic agents) to microprocessor fabrication (e.g. high-resolution patterning of polymers in photolithography). The proposed interdisciplinary research will develop polymers that respond to light in new ways with both fundamental and applied implications. The proposed work also integrates this research with education through two new programs: 1) encouraging STEM careers by involving a local community college in scientific research; 2) a high school science fair mentoring program.

With this award from the Major Research Instrumentation Program that is co-funded by the Chemistry Research Instrumentation and Facilities (CRIF) Program and the Office of Multidisciplinary Activities (OMA), Professor Arthur Utz from Tufts University and colleagues Terry Haas, Elena Rybak-Akimova, Clay Bennett and Samuel Thomas will acquire a single crystal X-ray diffractometer equipped with a CCD detector. The proposal is aimed at enhancing research training and education at all levels, especially in areas such as (a) mechanism-based design of selective, efficient, switchable receptors and catalysts for oxidations and other small molecule activation reactions; (b) design of functional organic materials; (c) design and development of catalysts for regioselective and enantioselective synthetic methods; (d) design of nanomaterials and nanocatalysts; (e) intermolecular interactions and self-assembly in fluorinated biomolecules; (f) functional polymer materials; (g) single molecules on surfaces; (h) biomimetic protein-based materials; and (i) design of cyclic peptides with enhanced affinity and selectivity of binding to their targets.

An X-ray diffractometer allows accurate and precise measurements of the full three dimensional structure of a molecule, including bond distances and angles, and provides accurate information about the spatial arrangement of a molecule relative to neighboring molecules. The studies described here will impact a number of areas, including organic and inorganic chemistry, materials chemistry and biochemistry. This instrument will be an integral part of teaching as well as research not only at Tufts University but also in a series of Boston area primarily undergraduate institutions that include Bridgewater State University, Emmanuel College and Suffolk University. Outreach to Braintree High School students and to deaf undergraduate students is being planned.

With support from the Chemical Measurement and Imaging (CMI) Program in the Division of Chemistry, Professor Samuel Thomas at Tufts University and his group will develop a new approach to signal amplification in fluorescent assays. Fluorescent sensors and assays are a key set of technologies in analytical science, and amplification of fluorescent response to a specific molecule or other stimulus is critical to the required high sensitivity of many technologies such as ELISA. There is a need, however, to develop new approaches that improve performance through increased quantitative accuracy, robustness in challenging environments, and reduced false positives and negatives. The objective of this project is to test the hypothesis that combining two forms of amplification: 1) chemical amplification of singlet oxygen (1O2) through photosensitization, and 2) light harvesting and exciton mobility will yield multiplicatively amplified fluorescent response that is useful in bioanalytical applications. The group will pursue the following two objectives to test their central hypothesis: 1) Demonstrate multiplicative amplification of fluorescence response of conjugated polymers substituted with traps that react with singlet oxygen, and 2) Use singlet oxygen-responsive polymers to detect target biomolecules at 1.0 pM or lower with high selectivity using sandwich assays. Successful realization of this approach would yield a unique and useful combination of features, such as a ratiometric response and the lack of a requirement for a large enzyme label, which overcomes limitations of current approaches and is potentially useful across a range of analytical applications. The broader impacts of the proposed work will be twofold: 1) a new method for amplifying fluorescent signal has the capability to improve to experimental techniques that rely on sandwich assays such as analysis of clinical samples and high-throughput drug discovery; 2) a program that integrates this research in organic photochemistry with demonstrations and experiments at Bunker Hill Community College, with which Prof Thomas already has a working relationship.

Signal amplification?processes that convert a small quantity of sample into a comparatively large readout?are an underlying key to the high sensitivity of modern sample analysis both in the clinic and in the field, in applications such as analysis of DNA or proteins by fluorescence. Limitations of current gold standard methods of amplification, however, are preventing the development of next-generation technologies that can detect targeted molecules at lower levels with reduced false positives and false negatives, especially outside the clinic, where there is a lack of control over environmental conditions. By combining two known methods of signal amplification with specially designed fluorescent materials, this proposed interdisciplinary research will yield a new approach to amplifying fluorescent signal that will be generally useful in a range of bioanalytical applications. Advantages of this approach over state-of-the-art technologies include 1) a more robust readout method of fluorescent signal, 2) no requirement for large enzyme labels, which can cause problems with both stability and sensitivity of an assay, to achieve amplification, and 3) increased sensitivity due to the combination of two forms of amplification. In addition to the benefit to society that such research achievements would provide, the group will also integrate their research into an outreach program at Bunker Hill CC, a nearby community college in Boston where 80% of the students belong to minority groups and over 50% are women, to develop experiments and demonstrations to give students hands-on experience with photochemistry, including using materials they develop in the research.

This project is funded by the Chemical Measurement and Imaging Program of the Chemistry Division at the National Science Foundation. Professors Samuel Thomas and Charles Mace of Tufts University, together with Professor Rajesh Menon of the University of Utah, are developing several new types of light-emitting nano-sized materials that respond to the molecule singlet oxygen. Singlet oxygen is an important molecule in light-driven processes such as photodynamic therapy and damage to plants upon overexposure to sunlight. One important outcome of this research is improved detection of singlet oxygen. Another important outcome of this research is better fundamental understanding of how the composition of fluorescent nano-sized materials affect their light emission properties and detection performance. This is important for other applications of light-emitting nano-sized materials. The broader impacts of this work include societal benefit from improved performance and reliability of analytical measurements involving fluorescent nanomaterials, and improved active learning of students in organic chemistry courses at Tufts University through a Peer-Led Team Learning (PLTL) pilot.

The goal of this proposal is to understand how the compositions of different fluorescent nanomaterials influence their response to singlet oxygen and yield generally applicable comparisons of key characteristics such as energy transfer efficiency, as well as improvements to the unsolved problems of singlet oxygen sensing and imaging. The objectives of this proposal are: 1) Prepare and characterize the fluorescence spectroscopy and energy transfer characteristics of three classes of water-dispersible singlet oxygen-reactive nanomaterials?i) conjugated polymer nanoparticles, ii) quantum dots, and iii) block copolymer micelles, and 2) In collaboration between PIs at Tufts and University of Utah, determine how the classes and compositions of these nanomaterials affect performance in: i) singlet oxygen detection, ii) use of singlet oxygen as a secondary analyte in bioassays, and iii) photoactivated fluorescence.

Non-Technical Abstract
Nano-sized materials that disassemble on demand can release therapeutic agents to sites where they are most needed. Light is an especially promising tool for triggering this on-demand carrier disintegration: it can pass through many barriers, be directed to precise locations, and be switched on and off easily. Most current biologically relevant technologies use high energy ultraviolet (UV) and visible light that do not penetrate tissue significantly. The research groups of Professor Samuel Thomas at Tufts University and Professor Vincent Rotello at the University of Massachusetts Amherst are working to overcome this limitation in therapeutic delivery by designing, developing, and understanding the ability of nano-sized materials to disintegrate upon exposure to low energy near-infrared (NIR) light. NIR light penetrates tissue to far greater depths than UV or visible light, providing access to new biological applications. They will gain understanding into how chemical design influences nanomaterial response to NIR light, and these materials will be further elaborated to target and deliver therapeutics to both cancer cells and bacterial biofilms. This research has the potential to benefit society through creation of new nanomaterials that harness NIR light to selectively deliver drugs and mitigate harmful side effects. Beyond the hands-on interdisciplinary training that this research provides to more graduate students, this project also provides targeted support for disadvantaged high school students to undertake research through the Tufts Summer Research Experience, thereby broadening participation in the STEM disciplines.

Technical Abstract
With support from the Biomaterials Program of the NSF Division of Materials Research, the goal of this research is to establish the ability of micelles in vitro to be degraded by singlet oxygen prepared in situ using NIR light. The overall project goal is to understand how chemical structures and polymer assemblies influence key individual chemical and physical material characteristics relevant to drug delivery. The first phase of this project will be to prepare and characterize polymers and micelles with a range of singlet oxygen-cleavable linkers, reactivities, and polymer topologies. The second phase of this project will be to understand how chemical structure and nanomaterial composition determines loading of cargo, stability in serum, photodegradation, and triggered release. The third stage of this project will evaluate the in vitro cytotoxicity and anti-bacterial activity of cargo-loaded NIR-degradable micelles. Further extension of this understanding of fundamental structure-property relationships will include micelles with targeting groups on their surfaces such as the RGD motif for cancer cells and quaternary ammonium cations for bacterial biofilms. Overall, this work has the potential to improve the efficacy of light-responsive drug-delivery systems, and in a broader context, advance the field of stimuli-responsive biomaterials by correlating chemical structures and their assemblies with loading, release, and in vitro activity.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.