NIR-Emissive Polymersomal Markers For Molecula-Level Detection Of Metastasis

Michael J Therien, Alan G. Macdiarmid Professor Of Chemistr
Chemistryduke University

Grant 5R01CA115229-04 from National Cancer Institute, IRG: ZRG1

Abstract: The detection of early carcinoma or dormant or latent metastatic tumor cells remains an elusive but important clinical goal. We seek to develop further revolutionary new nanotechnology that enables optically based detection of metastatic cancer cells. Towards this goal, we will further refine design criteria for near infrared (NIR) emissive polymersomes, a promising new soft matter nanoscale platform for in vivo diagnostic and drug-delivery applications. This program will develop (i) targeted nanoscale (diameter < 100 nm) NIR- emissive polymersomes, (ii) nanoscale NIR-emissive polymersomes having optimized emissive output, (iii) prototype targeted nanoscale vesicles in which the polymeric building blocks are based-upon FDA-approved materials, (iv) targeted NIR-emissive polymersomes with ideal cell-surface adhesion dynamics, and (v) methods and technology that provide not only new insights into metastatic disease, but define an evolvable nanoscale platform for in vivo dormant tumor cell detection, diagnosis, and treatment. These efforts involve correlating NIR fluorophore structure and photophysics, polymersome composition of matter, vesicle mechanical and biological properties, nanoscale NIR-emissive polymersome fluorescence output, and the nature of the cellular targeting motif, with in vivo function and efficacy. As such, the experimental approach we pursue is cross-cutting and integrative, encompassing supramolecular chemical synthesis, photophysical characterization, in vivo imaging, bioengineering, biology, and medicine. We will strive to establish design principles that will ultimately enable real-time detection and identification of limited target cell numbers under clinically relevant diagnostic conditions, and define new tools for the study of metastatic disease

Project start date: 2006-09-01

Project end date: 2010-07-31

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NIR-Emissive Polymersomal Markers For Molecula-Level Detection Of Metastasis

Michael J Therien, Alan G. Macdiarmid Professor Of Chemistr
University Of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104

Grant 5R01CA115229-02 from National Cancer Institute, IRG: ZRG1

Abstract: The detection of early carcinoma or dormant or latent metastatic tumor cells remains an elusive but important clinical goal. We seek to develop further revolutionary new nanotechnology that enables optically based detection of metastatic cancer cells. Towards this goal, we will further refine design criteria for near infrared (NIR) emissive polymersomes, a promising new soft matter nanoscale platform for in vivo diagnostic and drug-delivery applications. This program will develop (i) targeted nanoscale (diameter < 100 nm) NIR- emissive polymersomes, (ii) nanoscale NIR-emissive polymersomes having optimized emissive output, (iii) prototype targeted nanoscale vesicles in which the polymeric building blocks are based-upon FDA-approved materials, (iv) targeted NIR-emissive polymersomes with ideal cell-surface adhesion dynamics, and (v) methods and technology that provide not only new insights into metastatic disease, but define an evolvable nanoscale platform for in vivo dormant tumor cell detection, diagnosis, and treatment. These efforts involve correlating NIR fluorophore structure and photophysics, polymersome composition of matter, vesicle mechanical and biological properties, nanoscale NIR-emissive polymersome fluorescence output, and the nature of the cellular targeting motif, with in vivo function and efficacy. As such, the experimental approach we pursue is cross-cutting and integrative, encompassing supramolecular chemical synthesis, photophysical characterization, in vivo imaging, bioengineering, biology, and medicine. We will strive to establish design principles that will ultimately enable real-time detection and identification of limited target cell numbers under clinically relevant diagnostic conditions, and define new tools for the study of metastatic disease.

Project start date: 2006-09-01

Project end date: 2010-07-31

5R01CA115229-02 (2007): $299230

Charge-Transfer Dynamics And Energy Transduction

Michael J Therien, Alan G. Macdiarmid Professor Of Chemistr
University Of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104

Grant 5R01GM071628-04 from National Institute Of General Medical Sciences, IRG: BMT

Abstract: We seek to understand the roles that protein and cofactor conformational and chemical dynamics play in biological energy transduction through the design and synthesis of peptides and small proteins. Towards this goal, we will elaborate new classes of de novo proteins that differ radically from natural photosynthetic systems and electron transfer proteins that will ultimately enable us to decipher the essential engineering criteria important for the efficient conversion of photonic energy into electrochemical potential energy. These investigations exploit de novo tetra-a-helical proteins engineered to bind donor-spacer-acceptor supermolecules and covalently linked multicofactor assemblies. We will strive to correlate structure, function, and dynamics in these systems, utilizing information derived from computational protein design, peptide synthesis, supermolecular chemistry, and ultrafast dynamical experiments that include transient optical pump / optical probe and visible pump / IR probe spectroscopies; this work will provide a deeper, more active understanding of (i) protein folding, (ii) how local electrostatic forces that surround donor, acceptor, and chromophore can be independently modulated, (iii) functional aspects of electron and proton coupled electron transfer and radical generation in proteins, and (iv) the essential dynamics of protein mediated energy transduction.

Keywords: cofactor, conformation, electron transport, molecular dynamics, protein engineering, small molecule, bioenergetics, bioinformatics, biomimetics, chemical synthesis, chromophore, computational biology, computer simulation, ionic bond, molecular probe, peptide chemical synthesis, photochemistry, protein folding, protein structure function, synthetic protein, bioengineering /biomedical engineering, infrared spectrometry, optics

Project start date: 2004-08-01

Project end date: 2008-07-31

5R01GM071628-04 (2007): $253169

5R01GM071628-03 (2006): $261251

5R01GM071628-02 (2005): $268055

1R01GM071628-01 (2004): $268557

NIR-Emissive Polymersomal Markers For Molecula-Level Detection Of Metastasis

Michael J Therien, Alan G. Macdiarmid Professor Of Chemistr
Chemistryduke University

Grant 7R01CA115229-03 from National Cancer Institute, IRG: ZRG1

Abstract: The detection of early carcinoma or dormant or latent metastatic tumor cells remains an elusive but important clinical goal. We seek to develop further revolutionary new nanotechnology that enables optically based detection of metastatic cancer cells. Towards this goal, we will further refine design criteria for near infrared (NIR) emissive polymersomes, a promising new soft matter nanoscale platform for in vivo diagnostic and drug-delivery applications. This program will develop (i) targeted nanoscale (diameter < 100 nm) NIR- emissive polymersomes, (ii) nanoscale NIR-emissive polymersomes having optimized emissive output, (iii) prototype targeted nanoscale vesicles in which the polymeric building blocks are based-upon FDA-approved materials, (iv) targeted NIR-emissive polymersomes with ideal cell-surface adhesion dynamics, and (v) methods and technology that provide not only new insights into metastatic disease, but define an evolvable nanoscale platform for in vivo dormant tumor cell detection, diagnosis, and treatment. These efforts involve correlating NIR fluorophore structure and photophysics, polymersome composition of matter, vesicle mechanical and biological properties, nanoscale NIR-emissive polymersome fluorescence output, and the nature of the cellular targeting motif, with in vivo function and efficacy. As such, the experimental approach we pursue is cross-cutting and integrative, encompassing supramolecular chemical synthesis, photophysical characterization, in vivo imaging, bioengineering, biology, and medicine. We will strive to establish design principles that will ultimately enable real-time detection and identification of limited target cell numbers under clinically relevant diagnostic conditions, and define new tools for the study of metastatic disease

Project start date: 2006-09-01

Project end date: 2010-07-31

1R01CA115229-01A1 (2006): $327431

TIME RESOLVED INFRARED STUDIES OF ELECTRON TRANSFER COUPLED NUCLEAR ORGANIZATION

Michael J Therien, Alan G. Macdiarmid Professor Of Chemistr
University Of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104

Grant 5P01GM048130-100004 from National Institute Of General Medical Sciences, IRG:

Abstract: Electron transfer (ET) is one of Nature s most important reactions, playing key roles in respiratory and photosynthetic pathways that are of fundamental bioenergetic significance. Though relatively well understood as a reaction class, ET reactions are not understood in detail in terms of the molecular features that define reactivity ultrafast vibrational spectroscopy (infrared or coherent optical) will provide the first direct experimental probe that will help decipher how molecular motions are coupled to actual ET events. The reorganization energy (l),comprised of inner-sphere (high-frequency vibrational modes of the donor, acceptor, and medium) and outer-sphere (low-frequency vibrational modes of the solvent or bath) contributions, is of primary significance in determining how fast ET occurs in a given donor-acceptor system. Our goal to actually identify and measure the energy of vibrational modes that are key to an ET reaction coordinate represents an unexplored experimental frontier the potential to add to our fundamental knowledge of charge transfer chemistry as well as influence the theoretical framework that has been developed to describe ET reactions is enormous. Our work focuses on simple donor-acceptor complexes that undergo fast charge separation and/or change recombination reactions (kET greater than 2 x 10[12] s-1); the requirement of fast ET ensures that vibrational dephasing of excited-state reactants as well as ground- and excited-state ET products does not occur on our experimental timescale. Model systems that allow pair-wise examination of reaction center-type chromophores (such as porphyrins and quinones) feature prominently in this proposal. Similar to the intimate coupling of reorganization energy and reaction free energy, it is believed that the vibrational modes that activate chromophores for ET and accept energy in the photosynthetic reaction center play a central role in the highly efficient separation of an electron from a hole across a membrane during early photosynthetic events. Work completed to date has concentrated on utilizing optical pump-coherent optical probe experiments to study ET reactions that occur faster than the longitudinal relaxation time of the solvent. Such a coherently controlled ET reaction has recently been implicated in the long-range photosynthetic charge separation event. In addition to our experimental efforts designed to develop a fundamental understanding of coherence phenomena in ET reactions, other work exploits optical pump-IR probe experiments to probe the relationship between the readily identifiable high and low frequency chromophore vibrational spectroscopic tags (C-O and C-N stretching modes, arene and pyridinium ring breathing modes, porphyrin ruffling modes, etc.) and the ET reaction coordinate. Such detailed studies of how molecular vibrations are coupled to ET will both provide a new level of understanding of biological charge separation reactions as well as aid in the design of artificial systems that mimic photosynthesis, potentially impacting new energy storage technologies.

Keywords: chemical model, chemical structure function, electric field, electron transport, electronic spectra, ionic bond, molecular dynamics, porphyrin, chromophore, dielectric property, photochemistry, photosynthetic reaction center, protein structure, quinone, time resolved data, fluorescence resonance energy transfer, infrared spectrometry

Project start date: 2002-08-01

Project end date: 2003-07-31

TIME-RESOLVED INFRARED STUDIES OF ELECTRON-TRANSFER COUPLED NUCLEAR ORGANIZATION

Michael J Therien, Alan G. Macdiarmid Professor Of Chemistr
Institution:

Grant 5P01GM048130-040004 from National Institute Of General Medical Sciences, IRG:

Abstract: Electron transfer (ET) is one of Nature s most important reactions, playing key roles in respiratory and photosynthetic pathways that are of fundamental bioenergetic significance. Though relatively well understood as a reaction class, ET reactions are not understood in detail in terms of the molecular features that define reactivity ultrafast vibrational spectroscopy (infrared or coherent optical) will provide the first direct experimental probe that will help decipher how molecular motions are coupled to actual ET events. The reorganization energy (l),comprised of inner-sphere (high-frequency vibrational modes of the donor, acceptor, and medium) and outer-sphere (low-frequency vibrational modes of the solvent or bath) contributions, is of primary significance in determining how fast ET occurs in a given donor-acceptor system. Our goal to actually identify and measure the energy of vibrational modes that are key to an ET reaction coordinate represents an unexplored experimental frontier the potential to add to our fundamental knowledge of charge transfer chemistry as well as influence the theoretical framework that has been developed to describe ET reactions is enormous. Our work focuses on simple donor-acceptor complexes that undergo fast charge separation and/or change recombination reactions (kET greater than 2 x 10[12] s-1); the requirement of fast ET ensures that vibrational dephasing of excited-state reactants as well as ground- and excited-state ET products does not occur on our experimental timescale. Model systems that allow pair-wise examination of reaction center-type chromophores (such as porphyrins and quinones) feature prominently in this proposal. Similar to the intimate coupling of reorganization energy and reaction free energy, it is believed that the vibrational modes that activate chromophores for ET and accept energy in the photosynthetic reaction center play a central role in the highly efficient separation of an electron from a hole across a membrane during early photosynthetic events. Work completed to date has concentrated on utilizing optical pump-coherent optical probe experiments to study ET reactions that occur faster than the longitudinal relaxation time of the solvent. Such a coherently controlled ET reaction has recently been implicated in the long-range photosynthetic charge separation event. In addition to our experimental efforts designed to develop a fundamental understanding of coherence phenomena in ET reactions, other work exploits optical pump-IR probe experiments to probe the relationship between the readily identifiable high and low frequency chromophore vibrational spectroscopic tags (C-O and C-N stretching modes, arene and pyridinium ring breathing modes, porphyrin ruffling modes, etc.) and the ET reaction coordinate. Such detailed studies of how molecular vibrations are coupled to ET will both provide a new level of understanding of biological charge separation reactions as well as aid in the design of artificial systems that mimic photosynthesis, potentially impacting new energy storage technologies.

Keywords: chemical model, chemical structure function, electronic spectra, electron transport, infrared spectrometry, molecular dynamics, photosynthetic reaction center, porphyrin, quinone, time resolved data

COHERENT PHENOMENA IN ULTRAFAST BIOLOGICAL PROCESSES

Michael J Therien, Alan G. Macdiarmid Professor Of Chemistr
University Of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104

Grant 5P41RR001348-230076 from National Center For Research Resources, IRG: ZRG1

Keywords: biomedical facility

Project start date: 2004-08-01

Project end date: 2005-07-31

PHOTOPHYSICAL STUDIES OF CONJUGATED MULTIPORPHYRIN COMPOUNDS

Michael J Therien, Alan G. Macdiarmid Professor Of Chemistr
University Of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104

Grant 5P41RR001348-230090 from National Center For Research Resources, IRG: ZRG1

Keywords: biomedical facility, chemical conjugate, physics, porphyrin

Project start date: 2004-08-01

Project end date: 2005-07-31

INTRAMOLECULAR ELECTRON TRANSFER IN PORPHYRIN DIMERS, TIMERS AND PENTAMERS

Michael J Therien, Alan G. Macdiarmid Professor Of Chemistr
University Of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104

Grant 5P41RR001348-230097 from National Center For Research Resources, IRG: ZRG1

Keywords: biomedical facility, dimer, electron transport, intermolecular interaction, porphyrin

Project start date: 2004-08-01

Project end date: 2005-07-31