1993 — 1995 |
Rotello, Vincent |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Molecular Processes in Non-Newtonian Fluids @ University of Massachusetts Amherst
9315906 Rotello This award is the starter grant increment of Dr. Rotello's Postdoctoral Research Fellowship in Chemistry award. The focus of the research will be on molecular processes in non-Newtonian fluids. Solution organization will be used to model the ordered, yet dynamical environment created by protein and nucleic acid structures. The dynamic pockets formed in these solutions will provide many of the features present in enzymatic catalysis such as local concentration of reactants and conformational "pressure". The magnitude of these effects can be monitored by NMR and varied by modifying physical conditions such as spin rate and sample tube size. Molecular recognition and catalysis will also be studied in non-Newtonian solutions. %%% Non-Newtonian fluids are widespread in nature including blood, the interior of globular proteins and protoplasm. These typically aqueous polymer solutions vary their viscosity as a function of the applied stress. This research will address the fundamental nature of biological and synthetic polymers under non-Newtonian conditions. ***
|
0.915 |
1996 — 1999 |
Rotello, Vincent |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Synthetic Models of Flavoenzyme Activity @ University of Massachusetts Amherst
With funding from the Organic Dynamics Program, Professor Rotello of the University of Massachusetts-Amherst will investigate non-covalent bonding factors that influence the redox properties of flavoenzymes. For this investigation the principal investigator has prepared artificial binding sites which mimic the natural sites, but allow him to quantify the individual factors that are believed to affect the redox properties. The two major factors which are considered important are hydrogen bonding and pi stacking. Preliminary evidence suggests that the project will be successful. Understanding the details of enzymatic processes will provide scientists with the knowledge to modify paradigms and procedures for improved therapeutic drug efficacy. This project from a young investigator, if successful, will provide needed information on how flavoenzymes function. Since these enzymes are essential physiological moieties, this research has significant potential in the health related domain. These results may be useful to a broader scope of redox systems that are germane to organic materials and electronic devices.
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0.915 |
1997 — 2001 |
Rotello, Vincent |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Career: Model Systems For Flavoenzyme Activity. Recognition and Catalysis Within Sol-Gel Matrices @ University of Massachusetts Amherst
Professor Rotello's research focuses on three objectives: (1) incorporating flavin derivatives into transparent, silica-based, sol-gel matrices; (2) exploiting the electronic spectroscopy of flavins to probe sol-gel microenvironments; and (3) exploring the thermal redox and photocatalytic chemistry of bound flavins. Spectral properties of the incorporated flavins are correlated with viscoelastic measurements of the gel to identify changes in the flavin microenvironment during gelation and drying. The electrochemical and spectroelectrochemical behavior of the flavin incorporated in the matrix is compared with that in fluid solution to ascertain matrix induced changes in redox potential, while medium effects on redox activity are explored through stoichiometric oxidations of representative thiols and other biologically important functional groups. Educational activities include developing a molecular modeling component for large organic chemistry courses, continuing an outreach program designed to enhance high school students' interest in pursuing undergraduate degrees in the physical sciences, and mentoring undergraduate physical science majors in an integrated program designed to sustain and promote their interest in the physical sciences. With this CAREER award, the Organic Dynamics Program supports the research and educational activities of Professor Vincent Rotello of the Chemistry Department at the University of Massachusetts. Professor Rotello explores the incorporation of reactive molecules into glass-like environments, essentially forming artificial enzymes wherein the matrix plays the role ordinarily taken on by the amino acid backbone of a natural enzyme and the reactive molecule serves as the active site of the enzyme. These artificial enzyme systems offer the opportunity to probe various features of the processes effected by the natural enzymes and may also lead to the discovery of unique reaction chemistry distinct from that of the enzymes. Professor Rotello's educational activities include the development and integration into undergraduate organic chemistry courses of computer-assisted investigations of molecular structure. Through outreach programs, Professor Rotello encourages high school students to major in the physical sciences, and, once they are in college, he enhances and sustains the interest of undergraduate physical science majors through an integrated program of faculty seminars, field trips and interactive laboratory experiences.
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0.915 |
1999 — 2002 |
Rotello, Vincent |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
The Interplay of Recognition and Redox Processes. Electronically Controlled Devices and Surfaces @ University of Massachusetts Amherst
This project seeks to explore the interplay of recognition and redox processes, extending observations from the realm of host-guest chemistry into the arena of self-assembled monolayer surfaces (SAM's). Assembled on a gold surface, these SAM's will be subject to a variety of characterization methods including grazing angle infrared spectroscopy and cyclic voltammetry. Chemical modification of the surface will provide redox-functionalized moieties with the capability of binding specific guest molecules. Subsequent redox chemistry will be studied in order to assess the feasibility of fabricating such devices as a molecular "shuttle" and to explore control of surface properties such as charge and hydrophobicity/philicity. Ultimately, the creation of electronically responsive materials and devices may be possible.
With this Award, the Organic and Macromolecular Chemistry Program supports the research of Professor Vincent Rotello of the University of Massachusetts at Amherst. Professor Rotello's research involves the rational design of surfaces on a molecular level, using molecular assemblies that are electrically active. The principles that are identified in these experiments may find applications in new electronic devices based on the controlled formation of surfaces with predetermined structures and properties that respond to electrical stimuli.
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0.915 |
1999 — 2001 |
Rotello, Vincent M. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Model Systems For Flavoenzyme Activity @ University of Massachusetts Amherst
Flavoenzymes are proteins that use the flavin co-factor (FAD or FMN) to effect redox transformations and electron transfer. These enzymes function in a variety of essential biological roles, including metabolism, biosynthesis, and electron transport. The diversity of processes catalyzed by these protein is equally impressive, encompassing such divergent transformations such as thiol and amine oxidations, aromatic hydroxylation, and fatty acid dehydrogenation. In previous research, we have used model systems to explore fundamental aspects of flavoenzyme function, in particular the role of enzyme-co-factor interactions in modulating flavin redox processes. These models have allowed us to isolate and quantify specific interactions, and establish their role in determining flavoenzyme function. In our proposed research, we will extend these studies, using a synergistic application of synthetic receptors with chemical, electrochemical, spectroscopic and computational techniques. In chemical studies, we will synthesize receptors to explore the role of recognition processes in the mechanisms and energetics of the biomedically crucial thiol dehydrogenases. Concurrently, we will exploit the ability of electrochemical techniques to directly quantify the energetics of redox processes. In these investigations, we will synthesize receptors to determine the role of "traditional" non-covalent interactions, including hydrogen bonding, in the modulation of flavin redox processes. We will also create receptors to ascertain the role of micro- and macroscopic dipoles on flavin redox processes. These investigations, while focusing on the flavin redox system, will also provide insight into the general issue of the function of electrostatics in enzyme function. Spectroscopically, we will use a two-pronged approach to the study of flavin species. First, we will investigate the effects of recognition on the NMR, EPR and ENDOR spectra of flavins and flavin radicals. We will then use these spectra as calibration for computational methodology. From the synergy of these two methods, we will be able to quantify the effects of individual interactions on fundamental properties, including charge and spin density distributions. Using our model systems as a benchmark, we will also be able to extend with confidence our computational studies to actual enzymatic systems.
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1 |
2001 — 2003 |
Rotello, Vincent M. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Biomolecular Recognition Using Nanoparticle Receptors @ University of Massachusetts Amherst
DESCRIPTION: (Applicant's Description) Biomolecular Recognition Using Self-Optimizing Mu1tivalentNanoparticle Receptors Specific recognition of biomolecular Systems is a fundamental goal inbiomedical research. The ability to create efficient receptors for biomolecules allows us to fabricate biosensors that allow real-time monitoring central to the rapid diagnosis of imbalances and illnesses. Recognition of biomacromolecules, including proteins, polysaccharides, and nucleic acids, extends our ability to create diagnostic devices, while also providing an important tool for the modulation of cellularprocesses. To provide a general route for the creation of receptors for small molecules and macromolecules, we have created hosts based on nanoparticle scaffolds. These hosts are readily fabricated from self-assembled Monolayer-Protected Clusters (MPCs), either through direct functionalization during particle formation, or via subsequent place exchangereactions provide Mixed Monolayer Protected Clusters (MMPCs). In preliminary studies, we have demonstrated the ability of MMPCs to efficiently recognize both small molecules and macromolecules. Significantly, these receptors are dynamic, and can be templated through non-covalent interactions. In our proposed research, we will explore the fundamental aspects of these self-optimizing nanoparticle-based receptors, including the effect of monolayer structure, headgroups, and crosslinking on target recognition. Concurrently, we will apply these receptors to the recognition of guests possessing multiple size scales, from small molecule guests to peptides and protein surfaces. We will also explore the recognition of cellular structures, and the use of this recognition for both imaging and therapeutic applications.
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1 |
2001 — 2004 |
Candela, Donald (co-PI) [⬀] Lahti, Paul (co-PI) [⬀] Rotello, Vincent Tuominen, Mark [⬀] Russell, Thomas (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Acquisition of Instrumentation Cluster to Establish a Nanomagnetics Characterization Facility @ University of Massachusetts Amherst
CTS- 0116498 MRI: Acquisition of an Instrumentation Cluster to Establish a Nanomagnetics Characterization Facility
Mark T. Tuominen University of Massachusetts Amherst $320,000
Abstract
New nanofabrication methods are emerging that serve to provide a pathway to single-domain magnetic terabit technology. Such data-storage density is equivalent to storing 25 full-length DVD-quality movies on a disk the size of a quarter. This grant involves the acquisition of an equipment cluster for characterizing the properties of designer nanoscale magnetic materials. This facility will consist of a three instruments: a SQUID-based magnetometer, a high-resolution magnetic force microscope (MFM), and a swept-field NMR probe. These instruments provide complementary experimental information that advances the development of nanomagnetic materials fabricated using self-assembly and chemical techniques. The SQUID magnetometer will be used to obtain magnetization characteristics on arrays of nanoscopic magnetic elements, including hysteresis curves, switching fields, coercivity, saturation magnetization, and remanent magnetization. The MFM will provide local magnetic information on individual nanoscopic elements, heterostructures, and patterned nanomagnetic media. The swept-field NMR probe will developed at UMass and be used to identify different crystalline phases and crystalline orientations of magnetic nanostructures through the swept-field spectrum.
These instruments will impact many different research projects and provide an education and training environment for numerous users. The facility will be used to develop techniques to engineer the magnetic properties of terabit arrays of magnetic elements made by oriented diblock copolymer templates. Magnetic behavior will be manipulated through nanowire growth conditions, array scale, and hybrid patterning. These efforts will be augmented by supplemental neutron and x-ray scattering measurements at National Laboratory facilities. The scope of this research is broadened by international, federal, and industrial collaborations. Unique configurations of magneto-transport devices will be developed and investigated using laterally patterned magnetic arrays, magnetic heterostructures, and engineered magnetic nanoparticle assemblies. New synthesis and assembly approaches will be explored in studies of molecular magnetism. Education and training activities include instrumentation training and nanofabrication process training through the use of interactive digital-video.
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0.915 |
2001 — 2006 |
Rotello, Vincent Tuominen, Mark [⬀] Mccarthy, Thomas (co-PI) [⬀] Russell, Thomas (co-PI) [⬀] Penelle, Jacques (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Nanoscale Interdisciplinary Research Teams (Nirt): Copolymer Templates - a Self-Assembling Route to High-Density Arrays of Functional Nanostructures @ University of Massachusetts Amherst
This Nanoscale Interdisciplinary Research Teams (NIRT) project it to develop robust routes to produce high-density arrays of functional nanoscopic structures using nanoporous templates derived from diblock copolymer thin films. The diblock copolymer films used possess self-assembled cylindrical microdomains oriented normal to the surface of the film, with cylinder densities in excess of 1.0 x 10^12 /in^2. Selective degradation of the minor polymer block and cross-linking of the major block results in a polymer film having a high-density array of nanopores that serves as a template for the fabrication of functional arrays of nanoscopic structures. The project will expand the potential of this simple process by developing methods that give pore diameters ranging from the nanometer to the hundreds of nanometers. The research will advance the use of these templates to produce functional arrays of nanoscopic structures. This includes the use of metal electrodeposition in the template pores to produce ultrahigh-density arrays of magnetic nanowires for magnetic storage applications. The nanopore array can be patterned laterally using electron-beam lithography, to create magnetic nanowires and nanoparticle electron-transport studies. The nanoporous arrays will also be used as electrochemical nanoelectrode arrays, as reactive-ion-etching masks for silicon technology, and to produce glass nanopillars.
The project provides several unique educational opportunities including REU, RET, an interdepartmental nanoscience course, biweekly interdisciplinary meetings, and a technology-training program based on interactive digital video. This project integrates efforts from the academic and industrial sectors, with collaborations from national laboratories and international groups.
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0.915 |
2002 — 2005 |
Rotello, Vincent |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
The Interdependence of Redox and Recognition Processes @ University of Massachusetts Amherst
Professor Rotello and co-workers will initially study the effects of redox switching on the molecular recognition properties of a number of small molecules (imide-diaminopyridine dyads). They will use EPR, NMR, and density functional computational methods to determine the factors that control the efficiency of redox modulated molecular recognition processes. They will then apply redox modulated recognition process to the controlled formation of supramolecular polymers and polymer networks. This polymer work will involve development of redox active cross linkers for use in electronically controlled cross linking processes and redox controlled polymerization, both at surfaces and in solution.
With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. Vincent M. Rotello of the Department of Chemistry at the University of Massachusetts at Amherst. Dr. Rotello and his students will work on the development of small molecules which can be electrically induced to change their recognition and polymerization properties. The goal is to prepare materials which can be manipulated to change binding partners electronically or change oligomerization/polymerization state electronically. The organic based molecular devices developed will have the potential to function as information storage/switching systems in computers or sensors. Students trained during the course of this interdisciplinary work will gain skills needed by the pharmaceutical, polymer and speciality chemicals industries.
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0.915 |
2002 — 2005 |
Rotello, Vincent M. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Monolayer Protected Nanoparticles Flavoenzyme Models @ University of Massachusetts Amherst
DESCRIPTION: (provided by applicant) Site isolation and presentation of functionality are two key requirements for enzymatic catalysis. Researchers have developed synthetic systems that effectively mimic either the functionality or the isolation of enzyme active sites; creation of constructs that provide both of these attributes remains a significant challenge. We will use self-assembled monolayers (SAMs) on monolayer-protected gold clusters (MMPCs) to provide both the isolation and preorganization required to effectively replicate the behavior of flavoenzyme systems. There are three key thrusts to our proposed research: 1) The effective duplication of enzyme-cofactor interactions using the preorganization provided by the SAM, coupled with the control provided by the radial nature of the MMPC sidechains. 2) Fabrication of MMPC structures that provide effective isolation of cofactors buried within the SAM from solvent and other interfering species. 3) We will combine expertise gained from the above programs to design and fabricate fully functional mimics of the electron transferase family of flavoenzymes. These investigations will address key issues of recognition in water and control of enzyme mimic redox potentials, and will culminate with the creation of a functional electron shuttle designed to fully replicate the function of an electron transferase.
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1 |
2003 — 2004 |
Rotello, Vincent |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Ner: Dendrimer-Mediated Assembly of Nanostructures @ University of Massachusetts Amherst
The focus of this research involves four specific aims. First, the fabrication of gamma-Fe2O3 nanoparticles of varying diameters will be carried out and the particles will be decorated with cationic monolayers using a place exchange method. Second, using dendrimers, the self-assembly of theses particles will be explored and the ordering and interparticle spacing of the resulting materials will be determined using Small Angle X-Ray Scattering (SAXS). Third, the bulk properties of the materials will be quantified using SQUID magnetometry. Fourth, patterned surfaces will be created using electron beam lithography and these patterns will be employed to template nanocomposite assembly. The resulting systems will be studied using magnetic force microscopy.
With this Nanoscale: Exploratory Research (NER) award, the Organic and Macromolecular Chemistry Program and the Chemistry Office of Special Projects are supporting the research of Dr. Vincent M. Rotello of the Department of Chemistry at the University of Massachusetts, Amherst. Professor Rotello will focus his work on the use of nanoparticles for the production of well-defined magnetic materials. The interparticle distance of the materials will be controlled through self-assembly of superparamagnetic nanoparticles featuring cationic functionality using anionic dendrimers. In addition to the broader impact of the research in the materials area, the project presents an excellent site for the multidisciplinary training of graduate and undergraduate students.
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0.915 |
2004 — 2006 |
Bhatia, Surita (co-PI) [⬀] Thayumanavan, Sankaran [⬀] Rotello, Vincent Tew, Gregory (co-PI) [⬀] Coughlin, Edward (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Imr: Acquisition of a Gel Permeation Chromatography With Multiple Detection System For Polymer Research and Education @ University of Massachusetts Amherst
This proposal requests support for acquiring a gel permeation chromatography set-up with MALS, RI, and viscosity detectors for polymer materials research and education. The need for the instrumentation is based on significantly increased demand in using GPC for characterizing custom-designed polymers. This demand is evidenced by the fact that seven of the investigators listed in this proposal were hired by the University of Massachusetts within the past five years. The applications of these custom-designed polymers range from material science to biology. This instrument will also serve as a demonstration equipment for high school outreach programs targeted on science popularization. %%% This proposal requests a Gel Permeation Chromatography equipment to characterize polymeric materials. Several research groups at the University of Massachusetts are interested in the design and synthesis of polymers that are of interest in a wide variety of applications. These applications range from material science (e.g. light emitting diodes and photovoltaic materials) to biology (e.g. targeted delivery of chemotherapeutic drugs to cancer cells). On the educational side, this equipment will be used for demonstrations in a 'science popularization' outreach program that is being run by the PI and co-PIs of this proposal. ***
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0.915 |
2005 — 2006 |
Rotello, Vincent M. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Nanoparticles With Tailored Monolayers For Dna Transfection @ University of Massachusetts Amherst
[unreadable] DESCRIPTION (provided by applicant): Nucleic acid transfection is one of the most important tools in modern biology, and an emerging tool for biomedical applications. In our proposed research, we will use gold nanoparticles as transfection vectors. Gold nanoparticles possess three attributes that make them highly promising vectors: 1) Tunable size commensurate with biomolecular scales (4-10 nm); 2) Low inherent toxicity; 3) Stable and easily decorated monolayer surface, allowing control over surface charge and hydrophobicity, as well as facile conjugation to biotags such as peptides, and other functional molecules such as fluorescent dyes. Our proposed research features three specific Aims. These Aims are interrelated and will be performed concurrently, bringing to bear our expertise in synthesis, nanomaterials, and biology. In Aim 1, we will systematically vary the size of the particle and the structure of the monolayer. These studies will be used to create optimized transfection vectors, as well as exploring new vector-DNA unpackaging strategies. We will also explore the conjugation of peptide tags to the particles to provide enhanced uptake and localization of the DNA-MMPC aggregates. Aim 2 describes the strategies that will be used to quantify particle-DNA interactions, transfection efficiency, and toxicity. Aim 3 describes the use of microscopy to determine bottlenecks in the transfection process, providing information that will be used to design enhanced vectors. Rationale for R21 Mechanism. The major innovation of this proposal is the synergistic application of nanotechnology and synthesis to the area of transfection. The proposed research uses the gold core as a scaffold for the presentation of diverse functionalities, providing systems that should provide high transfection coupled with low toxicity. The R21 grant will provide an opportunity to explore the potentialities, directly providing enhanced vectors for in vitro studies. These studies will also lay the groundwork for the development of in vivo gene delivery systems that will be pursued in future studies. [unreadable] [unreadable]
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1 |
2005 — 2008 |
Rotello, Vincent |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Recognition-Controlled Polymer Self-Assembly @ University of Massachusetts Amherst
The Organic and Macromolecular Chemistry Program supports Professor Vincent M. Rotello at the University Massachusetts- Amherst whose work on the recognition-mediated assembly of macromolecular systems will provide unique capabilities for the bottom-up assembly of nano- and microstructures. One central theme of the current research program is the assembly of randomly substituted complementary systems into organized ensembles. This mode of self-assembly differs dramatically from the programmed interactions observed in DNA and protein structure. It likewise differs from simpler self-assembled systems both in terms of specificity and in the ability to balance specific favorable interactions with phase separation behavior. This level of control provides a new (but little understood) route to polymer self-assembly. In preliminary research funded earlier, Professor Rotello has shown that random systems featuring complementary functionality can produce systems featuring higher-order structures. In these studies, the unprecedented self-assembly of random copolymers into giant vesicles was demonstrated. In future studies, the structure and properties of these Recognition-Induced Polymersomes (RIPs) will be probed. Professor Rotello will also extend self-assembly studies to block copolymers, and explore the synthesis and properties of recognition element-functionalized alternating copolymers that feature regular intergroup spacing.
The Organic and Macromolecular Chemistry Program supports Professor Vincent M. Rotello whose research will provide a roadmap for the creation of self-assembled polymer microstructures. This insight will enhance the ability to create such diverse pragmatic systems as delivery devices and micro reactors. Moreover, the program is highly multidisciplinary, featuring tools and techniques from the fields of chemistry, materials science and physics. The graduate and undergraduate students working on this research will gain an integrated understanding of these diverse methodologies, providing them with powerful tools for their future careers.
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0.915 |
2005 — 2012 |
Rotello, Vincent Tuominen, Mark (co-PI) [⬀] Watkins, James [⬀] Russell, Thomas (co-PI) [⬀] Desu, Seshu (co-PI) [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Igert: Research and Innovation in Nanoscale Device Development @ University of Massachusetts Amherst
This Integrative Graduate Education and Research Training (IGERT) award supports interdisciplinary doctoral training in nanotechnology at the University of Massachusetts Amherst. The research and education activities span six science and engineering departments using a structure that ties advances in fundamental science to complementary coursework and practical experience in innovation and technology development. The program's intellectual merit and research emphasis is on the design, prototyping and market-oriented development of nanoscale devices through seamless integration of novel bottom-up processing schemes, including self-assembly, with conventional top-down approaches. Doctoral training is centered around three related research thrusts: nanoscale materials and processes; electronic applications; and biomedical and environmental applications. Specifically, IGERT students conduct research on the directed self-assembly of block copolymers, advanced lithography, novel deposition and metallization techniques, and their implementation in nanoelectronic devices, high-density data storage, biosensors and therapeutics. In addition to multidisciplinary technical, professional and product development training, the students team-train on annual Technical Challenge Projects that develop their ability to design and prototype technically and commercially feasible devices using nanotechnology. These projects include external research experiences at R&D facilities and fabrication centers located in the U.S. and abroad. Collaborators and advisors for the projects include TIAX and Lucent Technologies' Bell Laboratories. Additional activities focus on ethics, leadership and communication. The program's broader impacts include developing scientists and engineers that are comfortable working at disciplinary boundaries, possess a well-rounded mastery of nanoscience and engineering and have the ability to transform advances in basic science to functional materials and devices that can be commercialized to meet emerging technological and societal needs. IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to catalyze a cultural change in graduate education by establishing innovative new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries.
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0.915 |
2007 — 2010 |
Rotello, Vincent M. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Recognition and Presentation of Alpha Helices Using Nanoparticle Receptors @ University of Massachusetts Amherst
DESCRIPTION (provided by applicant): Surface recognition of proteins provides access to new therapeutic and diagnostic strategies. In our proposed research we will target helix-cleft protein-protein interactions such as p53-HDM2 using gold nanoparticle-based synthetic receptors. In these receptors, the nanoparticle monolayer will play an active role in the recognition process, exploiting the size scale (6-10 nm in diameter) and the ability of nanoparticles to be templated to target molecules. We will pursue two different strategies in our research: 1) Presentation of helices for the targeting of complementary protein clefts (e.g. HDM2);2) Templation of the nanoparticles to helices for recognition of exposed helices. The proposed research features three specific Aims. These aims are interrelated, bringing to bear synthetic, physical and biophysical methodologies. In these Aims, we will: Aim 1: Determine the scope and events involved in electrostatic binding of nanoparticles and their templation to ?-helices, focusing on the optimization of helix recognition. Aim 2: Covalently link the supramolecular peptide-particle assemblies developed in Aim 1, and target these conjugates to cleft-bearing proteins, including the p-53 binding domain of HDM2. These studies will focus on: 1) The ability of the particle to stabilize the helical structure of the peptide;2) The use of the particle monolayer to enhance the affinity of the receptors and to control the structure of the bound protein. Aim 3: Use nanoparticles as sensors for biomedically-relevant proteins. In these studies, particles will be templated to fluorophore-tagged peptides. The complexation of the peptide by the particle will quench the fluorophore. Fluorescent enhancement upon displacement of the peptide by the target protein will then be used to transduce binding. The selectivity of the protein-particle binding process will be applied in an array format to provide "chemical nose" sensing of proteins. Relevance: This research focuses on the creation of potential anti-cancer therapeutics and the detection of protein biomarkers for diagnosis of cancer and other disease states.
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1 |
2008 — 2013 |
Rotello, Vincent |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Bionanocomposites Through Protein-Mediated Assembly of Nanoparticles @ University of Massachusetts Amherst
With the support of the Organic Dynamics Program in the Chemistry Division, Professor Vincent Rotello at the University of Massachusetts- Amherst will develop robust and versatile strategies for the protein-mediated assembly of nanoparticles in which the protein and the particle play equal roles in terms of both assembly and materials properties. Previous studies on the self-assembly of nanoparticles using proteins, produced structured aggregates that displayed controlled optical and magnetic properties. This research will extend this study focusing on both the self-assembly process and the properties of the assembled materials. These properties are intermediate between bulk material and molecular compounds and strongly depend on the particle size and the shape of the nanoparticles. When assembled into organized ensembles, these materials gain collective properties that are often quite different from the isolated particles. This collective behavior is highly dependent on issues such as interparticle spacing and nanocomposite morphology. Combining nanocomposite behavior with the structural properties of proteins including size, shape, redox state, and structural stability provides a means to control this ensemble behavior. This collective modulation paves the way for pragmatic technological applications such as biosensors, as well as more ambitious prospects such as biocomposite devices and biological computing.
This research by Professor Rotello at the University of Massachusetts- Amherst is highly multidisciplinary featuring tools and techniques from the fields of chemistry, materials science, physics, and biology. One of the primary goals of nanoscience research is the preparation of controlled assemblies of nanoparticles, providing useful building blocks for devices such as biosensors, switches and high-density magnetic storage arrays. The graduate and undergraduate students working on this research will gain an integrated understanding of these diverse methodologies, enhanced through weekly meetings to discuss research. Further training as well as dissemination of research will be provided by sending the students to National Meetings including the Materials Research Society and the American Chemical Society. Finally, Professor Rotello has developed a multimodal partnership with Professor José Rivera (U. Puerto Rico, Rio Piedras) designed to enhance the development of minority researchers at many levels. This partnership includes faculty mentoring by Professor Rotello (with visits between UPR and UMass) and the regular exchange of graduate and undergraduate students between our respective groups as a tool for broadening their scientific and cultural education.
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0.915 |
2008 — 2009 |
Rotello, Vincent M. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Detection of Bacteria Using Nanoparticle-Polymer Sensors @ University of Massachusetts Amherst
[unreadable] DESCRIPTION (provided by applicant): The sensing of bacteria is a key tool for combating water contamination, food poisoning and infectious disease, as well for protection against biological warfare agents. In our proposed research, we will develop an array-based sensor for bacteria based on electrostatic conjugates formed from cationic gold nanoparticles and highly fluorescent anionic conjugated polymers. In these conjugates fluorescence emission from the polymer is quenched via energy transfer to the nanoparticle. In preliminary studies, we have demonstrated that the differential response observed with a set of three particles allowed identification of 13 bacteria featuring Gram negative and positive species, as well as differentiation between three different strains of E. coli. In our proposed research, we will focus on increasing the scope and sensitivity of this method, as well as test its applicability in complex media including serum and urine. Aim 1: Rotello will synthesize nanoparticles featuring a wide variety of headgroup functionality for targeting bacterial surfaces. The tailorable interfaces of these particles will provide the selectivity required for the creation of sensing systems. Concurrently, Bunz will synthesize conjugated polymer (CP) polyelectrolytes featuring complementary charges. These CPs will be customized in regards to affinity and fluorescent behaviour, providing multiplex sensing capabilities. Aim 2: Rotello and Bunz will develop prototype sensors for bacteria. Preliminary studies will explore the limits of detection for general bacteria sensing. Further studies will explore the degree of selectivity obtainable using MMPC-based receptors, with the ultimate goal the identification and quantification of pathogenic bacteria using chemometric protocols developed by Voigtman. Relevance: The goal of this research is to provide sensors that can rapidly identify bacteria (<5 min). These sensors should have applicability in testing of drinking water and identification of bioterrorism agents. We will also explore sensing in complex media including serum and urine, providing potential diagnostics for infections bacterial infections. Rationale for R21 Mechanism: The major innovation of this proposal is the creation of a highly sensitive displacement sensor for bacteria. The approach uses multivalent interactions between polymers and nanoparticles, coupled with the ability to engineer the surface properties of nanoparticles to provide controlled interactions with biological systems. The R21 grant will provide proof of concept studies demonstrating the utility of these sensors. If successful, these results will provide the foundation for sensors with applications in biomedical diagnostics that will be pursued under the R01 mechanism. PUBLIC HEALTH RELEVANCE: In our proposed research we will create sensors for the detection and identification of bacteria. These sensors will be useful for detecting bacteria in water supplies, providing protection against contamination from environmental or bioterrorist sources. These sensors will also be applied to blood models (serum), providing potential diagnostics for bacterial infections. [unreadable] [unreadable] [unreadable]
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1 |
2010 — 2011 |
Rotello, Vincent M. Vachet, Richard W (co-PI) [⬀] |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Multiplexed Tracking of Nanoparticles Using Laser Desorption/Ionization Mass Spec @ University of Massachusetts Amherst
DESCRIPTION (provided by applicant): The interaction of nanoparticles with biological systems is an important issue in biomedical and environmental sciences. In our proposed research we will exploit the selective laser desorption and ionization of ligands attached to nanomaterials to track cellular uptake and endosomal release of nanomaterials using mass spectrometry. In this approach the ligands serve as mass "barcodes", allowing the simultaneous tracking of multiple particles. In our proposed research we will take a multi-pronged approach to the systematic study of cellular uptake of nanoparticles that integrates analytical methodology development with synthesis and biology. Our research features three Aims that will be pursued in parallel: Aim 1: Rotello will fabricate nanoparticle with systematic variations in size and surface functionality. Aim 2: Rotello will incubate particles in multiplex fashion with different cell types, different lines of the same cell type, and isogenic variants of specific cell lines. Vachet will then use LDI to determine relative and absolute particle uptake. Once the fundamental parameters for cellular uptake have been established, Rotello and Vachet will use LDI-MS to quantify endosomal release. These studies will provide quantitative structure-activity correlations for cellular uptake and endosomal release of nanomaterials. Aim 3: Vachet will parametrically explore methods to optimize the sensitivity of LDI particle tracking and will investigate the analytical scope of this method. These results will provide enhanced probes for future applications of LDI for particle tracking in vivo. Our research will couple the nanoparticle synthesis and biological proficiency developed by the Rotello group with the instrumental and quantitative capabilities of Vachet. The goal of this R21 grant is two-fold: development and validation of multiplex analysis of cellular uptake of nanoparticles coupled with the application of this method to explore structure-activity properties of cellular uptake of nanomaterials. These results will be important in and of themselves in terms of delivery and diagnostic applications. Moreover, they will lay the foundation for the application of LDI for the tracking of nanoparticles in vivo and in the environment. PUBLIC HEALTH RELEVANCE: Tracking nanoparticles is an important issue in biomedical and environmental science. We will develop a strategy that allows simultaneous tracking of multiple types of nanoparticles and use this method to characterize cellular uptake of these materials.
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1 |
2010 — 2011 |
Rotello, Vincent M. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Nanoparticle-Stabilized Capsules as Drug Delivery Systems @ University of Massachusetts Amherst
DESCRIPTION (provided by applicant): Project Summary/Abstract Nanoparticle-Stabilized Capsules as Drug Delivery Systems Nanoparticle-stabilized capsules (NPSCs) provide a modular platform for the creation of delivery vehicles featuring a high carrier to payload ratio. In recent research, we have developed an alternative mode of NPSC stabilization that relies on stabilization of the capsule through supramolecular interactions between the nanoparticle shell and complementary hydrophobic "oil" components. Using this method, we have been able to produce nanocapsules featuring diameters as small as 100 nm. In our proposed research we will fabricate capsules based on this design and perform cell culture studies to determine their viability in delivery applications. Our proposed program features two Aims: Aim 1: We will fabricate NPSCs, focusing on the control of capsule size, stability, and functionalization. We will control particle size and stability through tailoring of particle-droplet and particle-particle interactions, as well as stabilize the NPSC shell through environmentally-responsive crosslinking. Aim 2: The efficacy of uncrosslinked and crosslinked particles for drug delivery will then be determined in a range of cell lines. Concurrently, we will determine the mechanism of payload release and determine the efficiency of drug delivery. We will also determine the efficiency of targeting using folate, RGD, galactose, transferrin and tamoxifen targeting. The goal of this two-year R21 grant is to develop strategies for the creation of nanometer-scale NPSCs and perform cell culture studies demonstrating the stability of these systems and their capabilities in drug delivery. These studies will provide proof-of-concept validation that will provide the foundation for animal model studies in future funding periods. PUBLIC HEALTH RELEVANCE: Project Narrative: Significance: Nanoparticle-stabilized capsules present a new means of delivering therapeutics to specific location in the body such as tumors or organs. In our proposed research we will develop new strategies to fabricate and tune particles for delivery applications, providing potential access to new therapeutic strategies.
|
1 |
2010 — 2014 |
Rotello, Vincent |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
International Collaboration in Chemistry: Synergistic Tailoring of Flavins and Quantum Dots For Solar Cell Applications @ University of Massachusetts Amherst
In this International Collaboration in Chemistry between US Investigators and their Counterparts Abroad (ICC) project funded by the Macromolecular, Supramolecular and Nanochemistry Program of the Chemistry Division and the Office of International Science and Engineering, Vincent Rotello of the University of Massachusetts at Amherst develop new strategies for assembling quantum dots to be used with flavin-modified polymers to effect charge separation in organic photovoltaic systems. The approach is to form nanopillars of quantum dots using nanoimprint lithography followed by post-processing to decrease interparticle spacing, to interface these particles with flavin-based acceptor macromolecules, and then to fabricate and test the aforementioned compounds in ordered heterojunction photovoltaic devices. This work includes an international collaboration with Prof. Ifor D. W. Samuel of the University of Saint Andrews, U.K. and Prof. Graeme Cooke of the University of Glasgow, U.K. Profs. Samuel's and Cooke's work will be funded by the Engineering and Physical Sciences Research Council (EPSRC). The broader impacts involve training graduate students, enhancing infrastructure for research and education through establishment of an international collaboration between universities in the U.S. and the U.K. The U.S. PI will endeavor to broaden participation of underrepresented groups in science by working with the LSAMP and SURE REU Programs at UMass.
Organic material-based solar cells show great technological promise but have significant drawbacks in terms of low efficiencies and significant processing problems. This research will enhance our fundamental understanding about how the integration of organic compounds and inorganic nanoparticles can be used to capture light and turn it into electrical energy. Through development of new chemical components and processing strategies, this research could lead to easier to process and less expensive solar cell technologies.
|
0.915 |
2011 — 2014 |
Rotello, Vincent M. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Multi-Channel Sensing Using Fluorescent Protein-Nanoparticle Sensors @ University of Massachusetts Amherst
DESCRIPTION (provided by applicant): The chemical nose/tongue approach presents a potential alternative to specific recognition and separations techniques. In this approach a sensor array is generated to provide differential interaction with analytes via selective receptors, generating a stimulus response pattern that can be statistically analyzed and used for the identification of individual target analytes and also analysis of complex mixtures. Recently, we have developed nanoparticle-fluorescent polymer sensors for identification of proteins, bacteria, and cancerous cells through a fluorophore-displacement mechanism as well as a highly sensitive nanoparticle-GFP based chemical nose strategy for protein detection in biofluid. Current chemical nose sensors for proteins and cell-surfaces are single channel, meaning a separate well or channel is required for each sensing element. This requirement for spatially distinct sensor elements complicates both microplate-based techniques and the application of array-based sensing in other venues, including microfluidics platforms and tissue staining. To overcome this limitation, we will exploit the spectral range of fluorescent proteins (FPs) to provide multi-channel fluorescence transduction for sensing applications. Multi-channel sensing will facilitate implementation of array-based sensing, allowing one well sensing while improving sensitivity through generation of ratiometric dadt. In this program, we will use the tools of supramolecular chemistry to synergistically engineer both the protein and AuNP quencher to provide highly efficient and versatile platforms for protein and cell surface sensing.
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1 |
2011 — 2014 |
Roberts, Susan (co-PI) [⬀] Bezanilla, Magdalena (co-PI) [⬀] Rotello, Vincent Minter, Lisa [⬀] |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Mri: Acquisition of Facsaria-Ii, a Next-Generation High-Speed Cell Sorter For a Flow Cytometry Core Supporting Interdisciplinary Research and Training @ University of Massachusetts Amherst
Flow cytometry is a powerful analytic technique that facilitates the characterization, quantification and/or isolation of cell populations based on innate or manipulated cellular attributes. Labeling cells externally or internally with fluorescently-conjugated antibodies or fluorescent vital dyes, or by genetically expressing fluorescent reporter molecules, all represent strategies for defining cell populations that may be differentiated using a flow cytometer.In recent years, BectonDickinson has made significant technological improvements, leading the field in creating the next-generation of cell sorters with its FACSAria (4) platform. A newer, user-friendly, bench-top high-speed cell sorter, the FACSAriaII, has digital electronics that allows high-speed analyses (70,000 events/second) based on up to 14 parameters, including cell size and internal complexity, with concomitant high-speed, simultaneous sorting of two or four populations, saving time and resources for users. Sample nozzles are easily interchanged to accommodate sorting large cells. Its fixed-laser alignment increases sensitivity, minimizes start-up time, improves reproducibility between experiments and enables automated daily quality control. It is capable of sorting cells aseptically for subsequent cell culture. The FACSAriaII platform is upgradeable, permitting economic configuration at the outset and retaining the flexibility to meet evolving user needs in the future. High-speed sorting, large cell size accommodation, increased sensitivity and upgradability make the FACSAriaII the best possible choice now and an excellent long-term investment.
This proposal describes the research of nine PIs as major users of a FACSAriaII, and an additional 10 minor users. Their projects, are broadly grouped by their requirements for one or more of the unique capabilities intrinsic to the FACSAriaII: i) high-speed sorting of unique target cell populations; ii) simultaneous, high-speed enrichment of multiple cell populations for further in vivo or ex vivo utilization; iii) high-speed sorting requiring multi-parameter stratification. Many of these PIs have optimized protocols in place, ensuring data will be obtained almost immediately upon acquiring a FACSAriaII. Reagent development is another important goal of many of the PIs, and acquiring a FACSAriaII will provide them with the capacity to advance and accelerate discovery for entire fields of research.
Chemical engineers will modify and analyze plant cells, on a per cell basis, to improve their production of cancer-treating compounds, or engineer bacterial quorum sensing for synthetic biology and industrial biotechnology. Biologists will be able to better understand the genes that regulate the structural dynamics of plant growth and chemists will use bacterial expression systems to generate and screen for synthetic allosteric ?switches? that can regulate cell death. Polymer scientists will track the efficiency and consequences of synthetic payload uptake into viable cells, while immunologists will recover and manipulate rare cell populations, transferring them from one host to another to better define mechanisms of disease, identify novel therapeutic targets, or advance vaccine development. Ongoing, diverse and, in many cases, interdisciplinary research will be strengthened and accelerated by the capabilities of a FACSAriaII high-speed cell sorter.
Many of the proposed research projects have applied objectives including potential translational benefits, such as identifying novel therapeutic targets and providing proof-of-principle data for novel delivery of payload. Additionally, some of these projects may have industrial or commercial applications. On-site access to a FACSAriaII will hasten progress toward these objectives. The group of major and minor users collectively trains many undergraduate and graduate students, and many of these through grant-funded interdisciplinary education and training, such as the University of Massachusetts/ Amherst Institute for Cellular Engineering and the Chemistry/Biology Interface. Looking forward, through outreach to sister colleges in the Five College Consortium, the Flow Core Facility will provide expanded opportunities for training undergraduate students in flow cytometric techniques, including students from Mt. Holyoke and Smith College, two all-women colleges that prepare a significant percentage of their undergraduate enrollment for advanced training in the STEM fields. Specifically, in conjunction with Smith College's Summer Science and Engineering Program, offered each year to high school-aged young women from across the country, a flow cytometry and cell sorting research module will be developed to introduce the next generation of women scientists to the power of single-cell analysis. Looking back, the University of Massachusetts/Amherst has a long-standing reputation for recruiting and retaining under-represented groups, in part through its lead role in the Northeast Alliance for Graduate Education and the Professoriate. This five-institution organization is committed to expanding opportunities for scientific graduate education and career advancement for under-represented groups. In 2008, the Cargnegie Foundation recognized the outreach efforts of the University of Massachusetts/Amherst when it designated UMass a Community Engaged University. The FACSAriaII, an instrument that combines powerful single-cell sorting and analysis with an accessible, user-friendly design will play an invaluable role in continuing these efforts.
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0.915 |
2011 — 2013 |
Bermudez, Harry Decaprio, Anthony P [⬀] Rotello, Vincent M. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Platform For High-Throughput Analysis of Protein Adducts For Carcinogen Exposure @ Florida International University
DESCRIPTION (provided by applicant): The long-term goal of this project is to develop a high-throughput technology that can characterize covalent protein and DNA modifications (adducts) induced by reactive carcinogens on a global basis with high sensitivity and specificity. Virtually all carcinogens, even the most inert, either contain an electrophilic center or undergo some level of oxidative metabolism to form reactive electrophiles. DNA and protein adducts are the products of the chemical reaction of such electrophiles with nucleophilic sites within these macromolecules. DNA adduction (including methylation and oxidative changes) has been widely implicated in mutation and carcinogenesis, while protein adducts (i.e., post-translational modifications) may have indirect roles in the mechanism of carcinogenesis if they involve DNA-related proteins or increase the rate of tumor promotion. In addition, such adducts are being explored as short- term, long-term, and/or cumulative markers of exposure to carcinogens. Current methods of adduct quantitation are expensive, highly chemical-specific, and labor-intensive. A technology for rapid and comprehensive profiling of macromolecular adduction in human subjects would be an important tool for carcinogen exposure and health risk assessment. This exploratory/developmental application proposes a proof-of-concept study to adapt three recently developed technologies, i.e., combinatorial chemical synthesis, antibody phage display, and microarray technology in a system to rapidly profile blood protein adducts of two important classes of carcinogens. Libraries of adducted peptides will be created to mimic structures formed in vivo in humans exposed to carcinogens. Adduct-specific scFv probes will be selected by screening with phage display libraries and validated with human blood specimens in an ELISA system. Results of ELISA-based adduct quantitation will be compared to those from conventional mass spectrometry-based analysis of blood protein adducts. If the proposed proof-of-concept studies are successful, expanded funding will be sought to develop a microarray-based global adduct detector for screening blood specimens from individual subjects. It is anticipated that the technology developed in this project will have wide applications for carcinogen exposure assessment, biomarker discovery, clinical diagnosis, and assessment of cancer treatment efficacies.
|
0.927 |
2012 — 2013 |
Rotello, Vincent M. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Enzyme Amplified Array Sensing of Proteins For Cancer Detection @ University of Massachusetts Amherst
DESCRIPTION (provided by applicant): Enzyme Amplified Array Sensing of Proteins for Cancer Detection Array-based sensing (the chemical nose/tongue approach) provides a versatile alternative to standard immunosensing strategies. In this approach a sensor array is generated to provide differential interaction with analytes via selective receptors, generating a stimulus response pattern that can be statistically analyzed and used for the identification of individual target analytes and complex mixtures. This methodology has been applied to biosensing, including proteins and cell surfaces. Application of these sensors, however, has been limited due to their low sensitivity. To provide enhanced sensitivity, we will use enzymes to create array- based sensors that provide amplification of the recognition event. In this Enzyme Amplified Array Sensing (EAAS) approach, the sensitivity of the array will be amplified through an enzymatic reaction, coupling the signal amplification of ELISA with the versatility of the chemical nose approach. Our research will develop and optimize EAAS sensors and apply them to two important targets in biosensing: Aim 1: We will create enzyme-nanoparticle conjugates to detect and identify changes in protein levels, and determine the ability of these systems to differentiate cell types and states (e.g. healthy, cancerous, metastatic) based on protein patterns in lysate. Aim 2: We will use murine models to determine the effectiveness of our sensor system for detection and phenotypic identification of cancer using tissue samples. The goal of this two-year R21 grant is to create highly sensitive and discriminating sensors for proteins and cell surfaces that will serve as platforms for cancer diagnostics and pathogen detection. Results from these studies will be used as the foundation for animal and clinical studies in future funding periods. PUBLIC HEALTH RELEVANCE: Enzyme amplified array-based sensing provide a versatile and efficient alternative to current immunosensing strategies. In our proposed research we will develop sensors for proteins with direct applicability to diagnostic systems for cancer.
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1 |
2012 — 2014 |
Rotello, Vincent M. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Intracellular Host-Guest Activation of Nanoparticle Therapeutics @ University of Massachusetts Amherst
DESCRIPTION (provided by applicant): Supramolecular chemistry provides tools for the assembly and actuation of molecular systems. The reversibility of association of host-guest systems enables facile assembly and disassembly coupled with 'lock and key' specificity. In our proposed research we will develop new therapeutics based on intracellular host-guest actuation of nanoparticle protherapeutics. This approach provides a new strategy for the creation of bioactive materials that will enable multiple targeting strategies inaccessible with current systems. In our proposed research, we will develop new nanoparticle protherapeutics based on nanoparticle-cucurbituril (CB) host-guest complexes. These complexes dissociate inside the cell in the presence of competitive binders for CB, unmasking and activating the cytotoxic particle therapeutic. This intracellular actuation process will be quantified using mass spectrometric techniques. We will then use the unique intracellular actuation process to enable new targeting approaches, including dual-targeting strategies that are expected to be highly specific to cells overexpressing multiple receptors.
|
1 |
2013 — 2017 |
Rotello, Vincent |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Plasmon-Enhanced Chiroptical Biosensors @ University of Massachusetts Amherst
Professor Vincent Rotello and his group at University of Massachusetts are supported by the Chemical Measurement and Imaging Program and the Macromolecular, Supramolecular, and Nanochemistry program in the Division of Chemistry and the Nano-Biosensing program in the Division of Chemical, Bioengineering, Environmental and Transport System (CBET) for an International Collaboration in Chemistry (ICC) grant to work with the groups of Graeme Cooke and Malcolm Kadodwala (University of Glasgow, UK) to create new biosensors based on plasmon-enhanced chiroptical sensing. This technique is highly sensitive and provides structural information of adsorbed analyte proteins. The team will apply this information-rich transduction technique to array-based sensing to develop highly responsive sensors capable of detecting minute changes in serum protein levels in a rapid and reproducible fashion. The proposed research program features both fundamental and applied research goals. Fundamentally, the researchers will to be explore nanoscale chiroptical behavior, developing new insights into the interactions of plasmonic fields with chiral systems. On the applied side, teh UMass and UGlasgow researchers will be tuning and optimizing synthetic systems, self-assembly, and nanopatterning to create more efficient sensor systems that employ the information-rich output of the chiroptical sensors to provide rapid and effective biosensing. This project will also provide excellent training for students: exchange programs between the groups will advance the research, draw together the complementary strands of the program, and transfer expertise between labs. Further efforts to extend the proposed research to minority participants will be made through the Louis Stokes Alliances for Minority Participation at UMass and the SURE REU program. The United Kingdom groups are supported by UK Engineering and Physical Sciences Research Council (EPSRC).
Different proteins interact differently with polarized light. The signature that is generated by these interactions provides both insight into protein structure and allows the protein to be identified. This technique is known as circular dichroism (CD), and is typically performed using large amounts of protein. In this proposed research the researchers will use nanopatterned materials to provide highly efficient application of CD to minute quantities of protein. The resulting technology will be applied to protein sensing, providing a potential tool for creating diagnostic devices for detecting disease through changes in protein level.
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0.915 |
2015 — 2018 |
Rotello, Vincent M. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Rapid Multi-Channel Serum Profiling For Cardiac Disease Using Fluorescent Nanosensors @ University of Massachusetts Amherst
? DESCRIPTION (provided by applicant): Rapid Multi-Channel Serum Profiling for Cardiac Disease using Fluorescent Nanosensors Rapid diagnosis of cardiac incidents is crucial to optimizing patient outcome and minimizing economic impact. Previous studies show that changes in level in major protein components of serum are associated with cardiac disease. In our previous research, we have shown that array-based chemical nose sensors can rapidly detect minute changes in serum protein levels. In our proposed research we will use nanoparticle-based sensor arrays to rapidly profile serum, focusing on the creation of effective sensor elements that use supramolecular hairpin motifs to provide a turn-on fluorescence response. The covalent linkage of the nanoparticle recognition element and fluorescent reporter will enable their use in flow systems, a capability we will use for the immobilization of these elements into devices. In our proposed research we will: Aim 1: Fabricate hairpin nanoparticle-fluorophore conjugates to provide multi-channel output and test their ability to detect changes in serum protein levels in a solution-based platform. Aim 2: We will immobilize our particles onto surfaces to provide prototype lateral flow and microfluidic sensing devices suitable for clinical and point-of-care use. These sensors will be tested and optimized using model sera. Aim 3: Use our solution and device sensor systems to profile acute coronary syndrome patients using serum samples provided by Smithline. These samples will be grouped into four diagnostic categories, with our studies seeking to correlate serum profile with patient. Samples will be obtained across the subject pool and longitudinally, enabling assessment of our strategy for tracking disease progression in individual subjects. The overall goal of this proposal is to develop prototype sensor systems for rapid POC diagnosis of cardiac disease. If effective, these sensors would provide additional diagnostic information that would enhance patient outcome and reduce expenses caused by unneeded tests and hospitalization. Beyond cardiac disease, these systems would have broad applicability for numerous disease states that have diagnostic changes in the serum proteome.
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1 |
2015 — 2018 |
Vachet, Richard Rotello, Vincent |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Multi-Mode Mass Spectrometric Imaging of Nanoparticle Stability @ University of Massachusetts Amherst
With support from the Chemical Measurement and Imaging Program in the Division of Chemistry, Professors Vachet and Rotello and their groups at University of Massachusetts, Amherst will develop a new mass spectrometry-based imaging approach to track nanomaterials in biological samples. Nanoparticles are increasingly used in applications that include drug delivery, sensing, imaging and therapy. In all cases, nanoparticles with the desired biological stability are required. Conversely, the increased presence of nanomaterials in commercial products raises concerns over the environmental and biological fate of nanomaterials. These new methods to be developed by Vachet and Rotello will provide quantitative insight into how to design nanoparticles of desired stability, from semi-stable materials used in drug delivery to much more stable materials that are required in commercial products. In addition to the envisioned scientific and societal impacts, the PIs propose to disseminate learned knowledge broadly through the National Nanomanufacturing Network (NNN) among the nanomanufacturing research, development and education community, as well as provide research opportunities to both undergraduate and graduate students, including those from underrepresented minority groups.
The intellectual merits of the proposed work lay in the development a dual mode imaging approach that can track nanoparticles based on both their core material and their functionalized monolayers. Specifically, Vachet and Rotello will use laser desorption/ionization (LDI) MS to track nanoparticles in tissues according to the monolayer molecules attached to the gold core and laser ablation (LA) inductively-coupled plasma (ICP) MS imaging to site-specifically monitor the extent to which nanoparticles stay still intact in biological systems. Vachet and Rotello will then use this new combined imaging approach to study the effect of nanoparticle surface chemistry, nanoparticle size, and tissue biochemistry on nanoparticle stability in tissues and organs from mice after intravenous (IV) injection of these NPs.
|
0.915 |
2017 — 2018 |
Rotello, Vincent M. |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Immunomodulation Through Nanocapsule-Mediated Cytosolic Delivery of Sirna @ University of Massachusetts Amherst
Project Summary/Abstract Immunomodulation through Nanocapsule-Mediated Cytosolic Delivery of siRNA RNA interference is a potentially powerful strategy for immunotherapy. A key barrier to this approach is the inability to effectively deliver siRNA to the cytosol: with current strategies the vast majority of siRNA remains trapped in endosomes and is ineffective. Nanoparticle-stabilized capsules (NPSCs) deliver siRNA directly to the cytosol in a membrane fusion-like process, bypassing endocytosis. We have demonstrated effective knockdown both in vitro and in vivo in the spleen, with the latter requiring significantly lower dosing than current delivery strategies. In our proposed research we will use in vitro and in vivo experiments to optimize the immunomodulatory properties of these vehicles, focusing on reducing inflammatory response by targeting the cytokine TNF-?. Our proposed program features two Aims: Aim 1: We will fabricate and optimize therapeutic siRNA-based NPSCs, focusing on maximizing cytosolar delivery efficiency, carrier capacity, and TNF-? knockdown to macrophages while minimizing toxicity and non-specific immune response. Aim 2: We will determine the efficacy of our delivery system in lipopolysaccharide- challenged mouse models of bacterial sepsis, via imaging and evaluation of anti- inflammatory effects following siRNA-bearing NPSC treatment. The goal of this proposal is to demonstrate the utility of the NPSC platform for immunomodulation. We will build upon the highly efficient cytosolar delivery of siRNA observed in our preliminary NPSC results, evaluating and optimizing their in vivo behavior. These studies will provide critical insights to the translational potential of this vehicle, providing essential preliminary results for applications in specific immune disorders.
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1 |
2017 — 2020 |
Rotello, Vincent M. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Supramolecular Bioorthogonal Nanozymes For Targeted Activation of Therapeutics @ University of Massachusetts Amherst
Project Summary/Abstract Supramolecular Bioorthogonal Nanozymes for Targeted Activation of Therapeutics In our proposed research we will create nanozymes?nanoparticles featuring protein-like size and surface properties that catalyze bioorthogonal processes using transition metal centers. These nanozymes will be used to activate prodrugs at tumor sites, using the bioorthogonal capabilities of the nanozyme to target tumors, generating therapeutics at the targeted tissue. We will assess these particles using in vitro models to determine intracellular therapeutic/imaging efficacy, targeting efficiency, and hemolytic properties. The particles will then be tested in vivo, assessing their efficacy in both imaging and therapeutic contexts. In our proposed studies, we will Aim 1: Fabricate nanozymes featuring different monolayer designs for optimizing particle loading and catalyst stability. We will quantify catalytic efficiency of these nanozymes for activating prodrugs, and determine their stability. Aim 2: Test the intracellular activity of nanozymes in cells through activation of pro- fluorophores and prodrugs. We will attach Her-2 targeting elements to the nanozymes and EGFR-targeting peptides to the polymeric prodrug delivery particles, and determine the ability to use dual AND targeting of nanozyme and carrier to target only cells that overexpress both receptors. Aim 3: Use targeted nanozymes to activate profluorophores and prodrugs at tumor sites using orthotopic breast carcinoma models. Aim 4: Differently targeted nanozymes and PEG/PLGA nanoparticles carrying prodrug will be used to provide therapeutic efficacy only at tumors overexpressing both targeted receptors, providing highly specific AND gate targeting. The goal of this research is to create therapeutic systems capable of high specificity through bioorthogonal chemistry. This research will build upon the supramolecular and nanomaterials strength of Rotello coupled with the cancer biology and animal model strengths of D. Joseph Jerry (UMass Vet. and Ani. Sci).
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1 |
2017 |
Mercurio, Arthur M Rotello, Vincent M. |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Nanosensor-Based Phenotypic Screening For Precision Therapy of Cancer Stem Cells @ University of Massachusetts Amherst
Project Summary/Abstract Nanosensor-Based Phenotypic Screening for Precision Therapy of Cancer Stem Cells Cancer stem cells (CSCs) have stem cells characteristics, including the ability to self-renew and populate new tumors. These cells are resistant to chemotherapy and are responsible for tumor recurrence and metastasis, making them important yet challenging therapeutic targets. In this U01 proposal, we will use a nanoparticle-based sensor to rapidly phenotype CSCs, using this information to screen for small molecule and nanoparticle therapeutics capable of differentiating CSCs to cells that are less aggressive and more susceptible to chemotherapeutics. Aim 1: Rotello will develop a robust nanoparticle-polymer high throughput-high content screening (HT-HCS) process for discriminating between CSC and non-CSC tumor cell models developed by Mercurio. Aim 2: Rotello will use the HT-HCS platform to identify small molecule and nanoparticle therapeutic agents with selective in vitro toxicity to CSC cells, and Mercurio will validate their ability to impact the in vitro and in vivo behavior of breast cancer cells. Aim 3: Mercurio will isolate CSCs from patient-dervied xenografts (PDX), and Rotello will use the HT-HCS platform to indentify precision therapeutic strategies in vitro that will be tested by Mercurio for their ability to hinder the initiation and recurrence of individual tumors. This ambitious research integrates the cancer biology expertise of Mercurio (UMass Worcester) with the nanomaterials and sensing capabilities of Rotello (UMass Amherst). The research will be greatly facilitated by the complementary team of researchers assembled for the project, as well as the extensive animal capabilities at Worcester and state of the art nanomaterials facilities at Amherst.
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1 |
2018 — 2021 |
Rotello, Vincent Vachet, Richard |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Multi Mode Mass Spectrometric Imaging of Nanomaterials and Their Biochemical Effects @ University of Massachusetts Amherst
With support from the Chemical Measurement and Imaging Program in the Division of Chemistry, Professors Vachet and Rotello and their groups at University of Massachusetts, Amherst are developing new approaches to tracking nanomaterials in biological samples. Nanomaterials are increasingly present in commercial products, and have potential to improve the efficacy of therapeutics through their use as drug delivery agents. To properly understand the potential biological consequences of such materials, new measurement methods are needed that can report on the distributions and biochemical effects of nanomaterials. Professors Rotello and Vachet are developing new imaging tools that can simultaneously monitor the distribution of nanomaterials in tissues while also providing site-specific information about their biochemical effects. The proposed imaging methods rely on sophisticated laser-based mass spectrometry which can also provide fundamental information about the interactions of light with nanomaterials. The new methods developed in this proposal can also provide information about how nanomaterial properties, such as size and composition, affect biochemistry and their distributions in vivo. A diverse group of undergraduate and graduate students involved in the project obtain training in cutting-edge mass spectrometry and nanotechnology, two areas of broad importance.
The Vachet/Rotello group is developing new imaging approaches that use matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) to simultaneously track nanomaterials, their associated molecules, and biomolecules (e.g. lipids, metabolites) in tissues. They are exploring how the MALDI matrix and the nanomaterial core material can work synergistically to enhance detection. They are also developing new computational approaches to fuse images obtained by laser ablation inductively-coupled plasma MS (LA-ICP MS) and MALDI MS. Target test applications focus on the effects of nanoparticle-stabilized capsules on tissue biochemistry. The PIs provide regular updates of their research and other related research on the National Nanomanufacturing Network (NNN) website, www.internano.org.
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.
|
0.915 |
2018 — 2021 |
Patel, Robin Rotello, Vincent M. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Crosslinked Nanosponges For the Topical Treatment of Wound Biofilms @ University of Massachusetts Amherst
Project Summary/Abstract Crosslinked Nanosponges for the Topical Treatment of Wound Biofilms The goal of the proposed research is the creation of therapeutics against multidrug-resistant biofilm infections. These infections are very difficult to treat: The refractory nature of biofilm infections make them highly resistant to standard antibiotics, a situation exacerbated by the development of antibiotic-resistant bacteria. In our research we will synergistically integrate the nanomedicine capabilities of Rotello with biofilm expertise of Patel. In preliminary research Rotello has developed crosslinked nanosponges imbibed with essential oil antimicrobials that penetrate and kill biofilm-based bacteria with minimal effect on host cells. Patel has created effective wound biofilm models that allow efficient assessment of therapeutics. In our proposed research we will develop new nanosponge therapeutics and test them against biofilms in vitro, in co-culture with mammalian cells, and finally in vivo. Aim 1: Rotello will fabricate and characterize polymeric nanosponges and optimize their activity against multi-drug resistant biofilms including S. aureus (MRSA) biofilm models. These nanosponges will be tested against mammalian cells in co-culture models, with the goal of maximizing antibacterial efficacy and minimizing mammalian cell toxicity. Aim 2: Rotello will screen therapeutics including antibiotics, quorum sensing inhibitors, and siderophores to create Generation 2 combination antibacterial agents. Aim 3: Patel will perform dosing and pre-clinical mouse studies of the optimized Generation 1 and 2 formulations, determining wound healing activity. Rotello will screen for inflammation.
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1 |
2020 — 2021 |
Rotello, Vincent M. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Rapid Multi-Channel Serum Profiling For Liver Disease Using Fluorescent Nanosensors @ University of Massachusetts Amherst
Project Summary/Abstract Rapid Multi-Channel Serum Profiling for Liver Disease using Fluorescent Nanosensors Rapid diagnosis of liver disease is crucial to optimizing patient outcome and minimizing economic impact. Current strategies for detecting liver damage (fibrosis/cirrhosis) use biomarker strategies that are expensive and difficult to translate into Point of Care (PoC) platforms suitable for monitoring of chemotherapy patients and diagnostics for the developing world. In preliminary studies we have demonstrated that simple polymer- based sensor arrays can generate serum ?signatures? that can be used to detect liver fibrosis with clinical relevance. In our proposed research we will: Aim 1: Fabricate hairpin polymer-fluorophore conjugates and use these as sensor elements to provide multi- channel outputs serum sensing. Aim 2: Immobilize our polymers onto surfaces to provide prototype sensing systems suitable for clinical and point-of-care use. These sensors will be tested and optimized using model sera. Aim 3: Apply our sensor systems to profile liver fibrosis using pathological samples provided by Rosenberg and Peveler. These studies will focus on detection and staging of liver fibrosis, using statistical methods developed by C. Rotello. Aim 4: Use proteomics with Vachet to characterize protein binding to the polymer sensors, providing mechanistic insight and potentially new biomarkers for fibrosis. The goal of this proposal is to develop prototype sensor systems for diagnosis of LIVER disease; effective achievement of this goal would provide strategies that could be translated to numerous additional disease states.
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2020 — 2023 |
Rotello, Vincent |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Collaborative Research: Accessing the Near Infrared Transparency Window For Triggered Delivery With Singlet Oxygen-Degradable Nanomaterials @ University of Massachusetts Amherst
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.
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0.915 |
2021 — 2024 |
Rotello, Vincent Vachet, Richard |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Multi-Modal Mass Spectrometric Imaging For Understanding the Biochemical Effects of Nanomaterials @ University of Massachusetts Amherst
With support from the Chemical Measurement and Imaging Program in the Division of Chemistry, Professor Richard Vachet, Professor Vincent Rotello, and their groups at the University of Massachusetts-Amherst are developing new methods to measure nanomaterials in biological samples. Nanomaterials are important in a growing number of technologies, ranging from consumer goods and industrial applications to biomedicine. To properly understand the consequences of such nanomaterials in each application, new measurement methods are needed that can report on their distributions and biochemical effects. Professors Vachet and Rotello are developing new imaging tools that can simultaneously provide both sets of information for nanomaterials in tissues. The proposed imaging methods rely on sophisticated laser-based mass spectrometry that can also provide fundamental information about the interactions of light with nanomaterials. The new methods developed in this grant are also leading to new ways to computationally combine data obtained from these new imaging methods and more traditional microscopy methods, thereby deepening the insight that can be extracted from these imaging methods. A diverse group of undergraduate and graduate students will be involved in the project, and these students will obtain training in cutting-edge mass spectrometry and nanotechnology, two areas of broad importance.
The Vachet/Rotello group is developing new imaging approaches that combine laser ablation inductively-coupled plasma mass spectrometry (LA-ICP MS) and matrix-assisted laser desorption/ionization MS (MALDI MS) to simultaneously track nanomaterials and biomolecules (e.g. metabolites, lipids) in tissues. They are exploring new multi-modal image segmentation approaches to more easily identify sub-organ specific molecular markers. They are also developing new computational methods to fuse images from LA-ICP-MS imaging, MALDI-MS imaging, and microscopy. Combining images from these modalities will improve spatial resolution and enhance the chemical information present in the images. They are also synthesizing new mass tags that can be conjugated to any nanomaterial to improve multi-modal imaging. New software that is developed in this project is made freely available to the research community.
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.
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0.915 |
2021 |
Rotello, Vincent M. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Targeting of Bio-Orthogonal Chemotherapeutic Nanozymes to Tumor-Associated Macrophages @ University of Massachusetts Amherst
Project Summary/Abstract Targeting of Bioorthogonal Chemotherapeutic Nanozymes to Tumor-Associated Macrophages In our proposed research we will use bioorthogonal chemistry to target tumor-associated macrophages (TAMs) in breast cancer, using bioorthogonal chemistry to turn them into ?drug factory? platforms for generation of chemotherapeutics at the tumor site. We will use our ?nanozyme? platform to encapsulate and protect transition metal catalysts (TMCs) within the monolayer of gold nanoparticles (AuNPs). These nanozymes will be targeted the mannose receptor strongly upregulated in TAMs. Systemic delivery of these nanozymes is anticipated to provide effective localization to TAMs that are highly accessible in tumors. Subsequent administration of non- toxic prodrugs will then provide uncaging of the chemotherapeutic localized to the tumor site. In our proposed research we will optimize the activity of our nanozyme platform. We will then engineer the nanozymes for selective TAM uptake through ?stealth? zwitterionic coating and suitable targeting elements. The targeting and therapeutic efficacy of the nanozymes will be quantified in vitro using mono- and co-culture models, Optimized particles will then be downselected for in vivo evaluation. Our specific aims are: Aim 1: Fabrication of Bioorthogonal Nanozymes. Goal: Engineering of monolayer structure to provide highly active and stable nanozymes. We will fabricate nanozymes coated with a zwitterionic layer to minimize non-specific uptake and mannose to target TAMs. We will optimize catalyst loading and stability in serum, and determine catalyst reactivity with prodrugs. Aim 2: In Vitro Activity and Targeting Studies. Hypothesis: Targeted nanozymes will provide highly cell-selective activation of prodrugs. We will quantify the intracellular activity of nanozymes in cells through catalytic uncaging of prodyes and prodrugs. Targeting efficacy to TAMs will assessed versus unpolarized macrophages and other cells, and in vitro therapeutic efficacy determined using co-culture models, optimizing the system based on specificity, efficacy/therapeutic window, and timing. Aim 3: Targeting of Prodrug Activation In Vivo. Hypothesis: Targeted nanozymes will localize prodrug activation to tumor sites, providing highly effective tumor therapy. We will use systemic injection of mannose- targeted nanozymes to activate profluorophores and prodrugs at tumor sites using 4T1 orthotopic breast carcinoma models. Quantitative tumor and intratumoral nanozyme distributions will be obtained using inductively-coupled mass spectrometry, and efficacy quantified by tumor size and mouse health. The overall goal of this project is to perform therapeutic ?jiu-jitsu?, using TAMs that normally protect tumors to provide launch points for highly localized therapeutic delivery to tumors. This bioorthogonal therapeutic strategy is expected to reduce off-target effects and increase therapeutic efficacy relative to current chemotherapeutic approaches.
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