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
Sponsored Links Lab Supply Mall http://www.labsupplymall.com
Grants awarded to Michael J Therien
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 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
5R01CA115229-02 (2007): $299230
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
Related Publications
Molecular Design of Porphyrin-Based Nonlinear Optical Materials. J Phys Chem A. 2008 Oct 31. [Epub ahead of print] PMID: 18973325 Using alpha-helical coiled-coils to design nanostructured metalloporphyrin arrays. J Am Chem Soc. 2008 Sep 10; 130( 36): 11921-7. Epub 2008 Aug 19. PMID: 18710226 Ultrafast excited-state dynamics of nanoscale near-infrared emissive polymersomes. J Am Chem Soc. 2008 Jul 30; 130( 30): 9773-84. Epub 2008 Jul 9. PMID: 18611010 Polymersomes: a new multi-functional tool for cancer diagnosis and therapy. Methods. 2008 Sep; 46( 1): 25-32. Epub 2008 Jun 20. PMID: 18572025 
Molecular symmetry and solution-phase structure interrogated by hyper-Rayleigh depolarization measurements: elaborating highly hyperpolarizable D2-symmetric chromophores. Angew Chem Int Ed Engl. 2008; 47( 16): 2978-81. No abstract available. PMID: 18338413 [PubMed] Synthesis of water-soluble poly(p-phenyleneethynylene) in neat water under aerobic conditions via Suzuki-Miyaura polycondensation using a diborylethyne synthon. Org Lett. 2008 Apr 3; 10( 7): 1341-4. Epub 2008 Mar 12. PMID: 18335946 [PubMed] Structure and dynamics of an extended conjugated NLO chromophore within an amphiphilic 4-helix bundle peptide by molecular dynamics simulation. J Phys Chem B. 2008 Feb 7; 112( 5): 1350-7. Epub 2008 Jan 12. PMID: 18189381 The effect of molecular orientation on the potential of porphyrin-metal contacts. Nano Lett. 2008 Jan; 8( 1): 110-3. Epub 2007 Dec 21. PMID: 18095730 [PubMed]
De novo design of a single-chain diphenylporphyrin metalloprotein. J Am Chem Soc. 2007 Sep 5; 129( 35): 10732-40. Epub 2007 Aug 10. PMID: 17691729 Molecular engineering of intensely near-infrared absorbing excited states in highly conjugated oligo(porphinato)zinc-(polypyridyl)metal(II) supermolecules. J Am Chem Soc. 2007 Aug 8; 129( 31): 9691-703. Epub 2007 Jul 13. PMID: 17629267 [PubMed] Carbodithioate-terminated oligo(phenyleneethynylene)s: synthesis and surface functionalization of gold nanoparticles. Org Lett. 2007 Jul 19; 9( 15): 2779-82. Epub 2007 Jun 29. PMID: 17602486 [PubMed] Temperature-dependent mechanistic transition for photoinduced electron transfer modulated by excited-state vibrational relaxation dynamics. J Phys Chem B. 2007 Jun 21; 111( 24): 6829-38. Epub 2007 May 10. PMID: 17489628 [PubMed] Tat-functionalized near-infrared emissive polymersomes for dendritic cell labeling. Bioconjug Chem. 2007 Jan-Feb; 18( 1): 31-40. PMID: 17226955 Electronic modulation of hyperpolarizable (porphinato)zinc(II) chromophores featuring ethynylphenyl-, ethynylthiophenyl-, ethynylthiazolyl-, and ethynylbenzothiazolyl-based electron-donating and -accepting moieties. Inorg Chem. 2006 Nov 27; 45( 24): 9703-12. PMID: 17112266 [PubMed] Structural studies of amphiphilic 4-helix bundle peptides incorporating designed extended chromophores for nonlinear optical biomolecular materials. Nano Lett. 2006 Nov; 6( 11): 2395-405. PMID: 17090064 Incorporation of designed extended chromophores into amphiphilic 4-helix bundle peptides for nonlinear optical biomolecular materials. Nano Lett. 2006 Nov; 6( 11): 2387-94. PMID: 17090063 Ethyne-bridged (porphinato)zinc(II)-(porphinato)iron(III) complexes: phenomenological dependence of excited-state dynamics upon (porphinato)iron electronic structure. J Am Chem Soc. 2006 Aug 16; 128( 32): 10423-35. PMID: 16895407 Exceptional near-infrared fluorescence quantum yields and excited-state absorptivity of highly conjugated porphyrin arrays. J Am Chem Soc. 2006 Jul 19; 128( 28): 9000-1. PMID: 16834350 Conjugated chromophore arrays with unusually large hole polaron delocalization lengths. J Am Chem Soc. 2006 Jul 5; 128( 26): 8380-1. PMID: 16802786 [PubMed] Broad spectral domain fluorescence wavelength modulation of visible and near-infrared emissive polymersomes. J Am Chem Soc. 2005 Nov 9; 127( 44): 15388-90. PMID: 16262400