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SER

Structure, Energetics and Reactivity

Photonics and Reactivity

Director:PhD Students:
Prof. Luis ArnautAlexandre Silva
Ana Catarina Lobo
Senior group members:Hélder Tão
Assistant Prof. Carlos Serpa
Ana Mata
Dr. Fábio SchaberleMaria Inês Mendes
Dr. Ligia Gomes-da-SilvaAndré Luz
Polythea
Post-doctoral fellows:
Dr. Catarina Jesus

PRL_team

Mission

The Photonics and Reactivity Lab is a place for initiative and creative thinking, to explore less-traveled paths and dare question conventions using the tools of science. The unifying theme is the use of light to open new frontiers. Together with various labs in the Coimbra Chemistry Centre and elsewhere, we design new molecules and customize equipment to explore our original ideas.
The first drug patented by a Portuguese university that reached clinical trials was designed in our laboratory. We are also at the origin of a technology introduced in the aesthetics market and tested for medical applications. We cherish innovative solutions and encourage spin-offs of lab members, but believe that long-lasting solutions to human needs must be rooted in fundamental science.

Highlights

Photoinduced reactivity

The dogma of chemical reactivity is that, for elementary reactions, higher barriers lead to slower reactions. In Nature Communications 9 (2018) 2903 we present intramolecular electron transfers that become faster as their apparent activation energies increase, and oppose the “inverted region” energy dependence predicted by Marcus. The deficiencies of Marcus theory are exposed and an alternative model for electron transfer is discussed. On-going research calls for a change in paradigm in the theory of electron transfer reactions.

Photodynamic therapy

PDT combines a photosensitizer, light and molecular oxygen to generate cytotoxic reactive oxygen species that kill cells. As explained in the highly cited paper published in Photochem. Photobiol. Sci. 14 (2015) 1756 (top 1% of the academic field of Biology & Biochemistry), PDT has both a local and a systemic effect. The elimination of the primary tumor and control of metastasis were achieved with a bacteriochlorin photosensitizer named redaporfin and designed by us, as published in Eur. J. Cancer 51 (2015) 1822. The mechanisms through which PDT with redaporfin kills cancer cells were presented in EMBO J 37 (2018) e98354, showing that the ER/GA play a role upstream of mitochondria in the lethal signaling pathway.

Photoacoustics and therapy

The ability to produce high-pressure high-intensity ultrasound pulses using nanosecond laser pulses, developed in our laboratory, was applied to the non-invasive delivery of hyaluronic acid as dermal filler for facial rejuvenation. A face-split, randomized, placebo-controlled, double-blind study to investigate passive versus active hyaluronic acid administration, published in Aesth. Plast. Surg. (2018) DOI 10.1007/s00266-018-1208-9, revealed that this procedure is safe and leads to unambiguous facial rejuvenation. Ultrasound pulses generated with picosecond laser pulses are capable of temporarily permeabilize cell membranes and enable gene transfection with negligible cytotoxicity. Photoacoustic transfection of a plasmid DNA encoding Green Fluorescent Protein in COS-7 monkey fibroblast cells attained an efficiency of 5% in 10 minutes at 20 °C (to appear soon).

Protein folding

Protein (miss)folding is at the origin of various neurological diseases. The folding dynamics and energetics of β-helical segments in proteins were described in J. Phys. Chem. B 122 (2018) 3790, using photoinduced pH jumps with photoacoustic detection, and revealed the role of salt bridges and cation-π interactions. The singular fluorescence from aggregated myeloid fibrils has eluded observation, but was unambiguously identified and characterized (to appear soon).

Imaging

The new frontiers of medical imaging and treatment demand the ability to visualize microstructures that target the diseased tissue. By imaging where, when and how much of a marker chromophore appears in the target tissue, it becomes possible to refine basic preclinical research and improve therapy. In J. Med Chem. 59 (2016) 4688 we present rationally-designed near-infrared fluorophores developed in our group to image 1 mm tumors not visible with the naked eye. Current developments in our group focus on molecular contrast agents for photoacoustic tomography.

Photophysics

The fundamentals of light interaction with matter (and molecules) still raise technical challenges and controversies. The accurate measurement of light doses in PDT was explained in Photodiagn. Photodyn. Ther. 23 (2018) 75. The transfer of photon momentum when light crosses media with different refractive indexes (n), manifested in the nanometric deformation of the interface between the two media, was clearly separated from thermoelastic expansion and shown to be consistent with the Minkowski momentum pM=pairn (to appear soon).



On-going projects

The Integrated Initiative of European Laser Research Infrastructures
H2020-INFRAIA-2014-2015, 654148 — LASERLAB-EUROPE
Funding (2015-2018): 10.000.000 € (under management of SER PI: 110.190 €)
Portuguese PI: Luis Arnaut

Photoacoustic Permeabilization of Biological Barriers – A Window for Drug Delivery and Gene Transfection
FCT/PTDC/QEQ-MED/3521/2014, 2016-2019
Funding (2016-2019): 232.800 € (under management of PI: 166.800 €)
PI: Luis Arnaut

LaserLab Portugal
FCT/ROTEIRO/0152/2013
Funding (2017-2020): 2.510.290 € (under management of SER PI: 1.864.190 €,
Coimbra PI: Luis Arnaut

PhD Programme on Medicinal Chemistry
FCT/ PD/00147/2013
Funding (2014-2022): 100.000 € and 24 PhD scholarships (under management of SER PI: 100.000 € and 12 PhD scholarships)
Coimbra PI: Luis Arnaut

POLYTHEA – Design and photo-optimization of photosensitizer for human health and food security applications
H2020, MSCA-ITN-EJD
Funding (2018-2022): 2.548.256 € (under management of SER PI: 265.227 €)
Coimbra PI: Ligia Gomes-da-Silva

Granted and licensed patents

Low molecular weight derivatives of carboxamide halogenated porphyrins, namely chlorins and bacteriochlorins, and their applications in photodynamic therapy
G. P. N. Costa, N. P. F. Gonçalves, C. J. P. Monteiro, A. C. R. Abreu, H. T. Soares, L. B. Rocha, F. A. Schaberle, M. M. Pereira, L. G. Arnaut Moreira
Luzitin SA and University of Coimbra. PT patent application no. 20151000038067. 7/5/2015. PCT/IB2016/052606. WO2016178191.
Granted and in force: European Union
Pending: all other territories
Licensed to Luzitin SA

Atropisomers of halogenated tetraphenylbacteriochlorins and chlorins and their use in photodynamic therapy
N. P. F. Gonçalves, T. P. C. M. Santos, G. P. N. Costa, C. J. P. Monteiro, F. A. Schaberle, S. C. Alfar, A. C. R. Abreu, M. M. Pereira, L. G. Arnaut Moreira
Luzitin SA and University of Coimbra. PT patent application no. 20151000023583, 20/3/2015. PCT/IB2016/051552. WO2016151458.
Pending: all territories.
Licensed to Luzitin SA

Device for the efficient delivery of compounds to or through the skin or biological barriers, using light-absorbing thin films
Gonçalo F. F. Sá, Carlos A. L. Serpa Soares, Luis. G. S. Arnaut Moreira
Universidade de Coimbra. PT Patent Application no. 105635, 19/04/2011.
PCT/PT2012/000013, 19/04/2012. WO/2012/144916.
Granted and in force: Australia, Canada, China + Hong Kong, Colombia, European Union (Austria, Belgium, Czech Republic, Denmark, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Lithuania, Netherlands, Poland, Portugal, Slovenia, Spain, Sweden, United Kingdom), Israel, Japan, Mexico, Norway, Russia, South Africa, South Korea, Switzerland, Turkey, United States.
Pending: Brazil, India.
Licensed to LaserLeap SA

Process for Preparing Chlorins and their Pharmaceutical Uses
L. G. Arnaut Moreira, M. M. Pereira, S. J. Formosinho, S. Simões, G. Stochel, K. Urbanska
Universidade de Coimbra. UK Patent Application no. 0819594.3, 24/10/2008.
PCT/PT2009/000057, 22/10/2009. WO/2010/047611.
Granted and in force: Australia, Canada, China, India, European Union (Austria, Belgium, Denmark, France, Germany, Greece, Ireland, Italy, Luxemburg, Netherlands, Poland, Portugal, Spain, United Kingdom), Japan, Norway, Russia, South Africa, Switzerland, United States.
Pending: Brazil.
Licensed to Luzitin SA

Nouveaux dérivés de porphirine, notamment chlorines et/ou bactériochlorine, et leurs applications en thérapie photodynamique
M. M. Pereira, L. G. Arnaut, S. J. Formosinho, C. J. P. Monteiro
Universidade de Coimbra. Patente francesa nº 0412149, 16/11/2004.
PCT/EP/012212, 10/11/2005. WO2006/053707.
Granted and in force: Australia, Canada, China, India, European Union (Austria, Belgium, Denmark, France, Germany, Greece, Ireland, Italy, Luxemburg, Netherlands, Poland, Portugal, Spain, United Kingdom), Japan, Norway, Russia, South Africa, Switzerland, United States.
Pending: Brazil.
Licensed to Luzitin SA

Spin-offs

Luzitin SA – Founded in 2010, Luzitin is a pharmaceutical company focused on the pursuit of innovative solutions for photodynamic therapy and photodiagnosis
LaserLeap SA – Founded in 2011, LaserLeap is a biotech company with a proprietary drug-delivery technology in the aesthetics market.

Major equipment

Our group members are actively involved in the management and use of strategic infrastructures of the University of Coimbra, namely:
· Coimbra Laser Laboratory
· Nuclear Magnetic Resonance Laboratory
· Advanced Optical Microscopy
· ICNAS Preclinical Imaging Facility

Through these facilities and in our labs, the group regularly uses
– Absorption, fluorescence and phosphorescence from the UV through the NIR.
– Time-correlated single photon counting and fluorescence up-conversion (under installation) with time-resolution between 1 ps and 100 ns
– Transient absorption with time-resolution from 100 fs to 100 µs.
– 2D IR spectroscopy with fs resolution (under installation).
– Photoacoustic calorimetry with time resolution between 5 ns and 10 µs.
– Fluorescence, confocal and multiphoton microscopies.
– Photoacoustic tomography (under installation).
– Cell culture lab with flow cytometry and Western Blot.
– Incident photon-to-current efficiency and solar simulator equipment
More than half of the lab members are qualified for designing and executing small animal experiments. Such experiments are regularly conducted, after approval by ethical and regulatory committees, in the animal facilities of CNC (Center for Neuroscience and Cell Biology) and ICNAS (Institute of Nuclear Sciences Applied to Heath), both at the University of Coimbra.

Selected publications

Since 2013

“Higher activation barriers can lift exothermic rate restrictions in electron transfers and enable faster reactions”
K. K. Mentel, A. Serra, P. E. Abreu, L. G. Arnaut, Nature Communications 9 (2018) 2903
DOI: 10.1038/s41467-018-05267-5

“Photodynamic therapy with redaporfin targets the endoplasmic reticulum and Golgi apparatus”
L. C. Gomes-da-Silva, L. Zhao, H. Zhou, A. Sauvat, P. Liu, L. Bezu, S. Durand, M. Leduc, G. Pierron, F. Loos, B. Sveinbjørnsson, Ø. Rekdal, G. Boncompain, F. Perez, L.G. Arnaut, O. Kepp, G. Kroemer, EMBO J., 37 (2018) e98354
DOI: 10.15252/embj.201798354

“Split-face, randomized, placebo-controlled, double-blind study to investigate passive versus active dermal filler administration”
M. J. Freire-dos-Santos, R. Carvalho, L. G. Arnaut, Aesth. Plast. Surg. (2018) available online.
DOI: 10.1007/s00266-018-1208-9

“One peptide reveals the two faces of a-helix unfolding-folding dynamics”
C. S. H. Jesus, P. F. Cruz, L. G. Arnaut, R. M. M. Brito, C. Serpa, J. Phys. Chem. B 122 (2018) 3790.
DOI: 10.1021/acs.jpcb.8b00229

“Assessment of the actual light dose in photodynamic therapy”
F. A. Schaberle, Photodiagn. Photodyn. Ther. 23 (2018) 75.
DOI: 10.1016/j.pdpdt.2018.06.009

“Ultrafast Dynamics of Manganese (III), Manganese (II), and Free-Base Bacteriochlorin: Is There Time for Photochemistry?”
F. A. Schaberle, A. R Abreu, N. P. F. Gonçalves, G. F. F. Sá, M. M. Pereira, L. G Arnaut, Inorg. Chem., 56 (2017) 2677-2689.
DOI: 10.1021/acs.inorgchem.6b0287

“Phthalocyanine Labels for Near-Infrared Fluorescence Imaging of Solid Tumors”
A. C. S. Lobo, A. D. Silva, V. A. Tomé, S. M. A. Pinto, E. F. F. Silva, M. J. F. Calvete, C. M. F. Gomes, M. M. Pereira, L. G. Arnaut, J. Med. Chem., 59 (2016) 4688-4696.
DOI: 10.1021/acs.jmedchem.6b00054

“Pro-oxidant and antioxidant effects in Photodynamic Therapy: Cells recognize that not all endogenous ROS are alike”
H. Tão, J. R. S. Campos, L. C. Gomes-da-Silva, F. A. Schaberle, J. M. Dabrowski, L. G. Arnaut, ChemBioChem, 17 (2016) 836-842.
DOI: 10.1002/cbic.201500573

“Intracellular singlet oxygen photosensitizers: On the road to solving the problems of sensitizer degradation, bleaching and relocalization”
    E. F. F. Silva, F. M. Pimenta, B. W. Pedersen, F. H. Blaikie, G. N. Bosio, T. Breitenbach, M. Westberg, M. Bregnhøj, M. Etzerodt, L. G. Arnaut, P. R. Ogilby, Int. Biol., 8 (2016) 177-193.
    DOI: 10.1039/C5IB00295H

“Assessment of lifetime resolution limits in time-resolved photoacoustic calorimetry vs. transducer frequencies: setting the stage for picosecond resolution”
    F. A. Schaberle, M. J. Francisco de Assis, L. A. Reis, L. G. Arnaut, Photochem. Photobiol. Sci., 15 (2016) 204-2010.
DOI: 10.1039/C5PP00397K

“Photodynamic Therapy (PDT) of Cancer: From a Local to a Systemic Treatment”
    J. M. Dabrowski, L. G. Arnaut, Photochem. Photobiol. Sc., 14 (2015) 1765-1780.
    DOI: 10.1039/C5PP00132C

“Elimination of primary tumours and control of metastasis with rationally designed bacteriochlorin photodynamic therapy regimens”
    L. B. Rocha, L. C. Gomes-da-Silva, J. M. Dabrowski, L. G. Arnaut, Eur. J. Cancer, 51 (2015) 1822-1830.
    DOI: 10.1016/j.ejca.2015.06.002

“Photodynamic Therapy Efficacy Enhanced by Dynamics: The Role of Charge Transfer and Photostability in the Selection of Photosensitizers”
    L. G. Arnaut, M. M. Pereira, J. M. Dabrowski, E. F. F. Silva, F. A. Schaberle, A. R. Abreu, L. B. Rocha, M. M. Barsan, K. Urbanska, G. Stochel, C. M. A. Brett, Chem. Eur. J., 20 (2014) 5346-5357

“Stratum corneum permeabilization with photoacoustic waves generated by piezophotonic materials”
    G. F. F: Sa, C. Serpa, L. G. Arnaut, J. Control. Release, 167 (2013) 290-300
    DOI: 10.1016/j.jconrel.2013.02.005


Classical collection


“Mechanisms of singlet-oxygen and superoxide-ion generation by porphyrins and bacteriochlorins and their implications in photodynamic therapy”
E. F. F. Silva, C. Serpa, J. M. Dabrowski, C. J. P. Monteiro, S. J. Formosinho, G. Stochel, K. Urbaska, S. Simões, M. M. Pereira, L. G. Arnaut, Chem. Eur. J. 16 (2010) 9273-9286.

“Photoacid for extremely long-lived and reversible pH-jumps”
    R. M. D. Nunes, M. Pineiro, L. G. Arnaut, J. Am. Chem. Soc., 131 (2009) 9456-9462.

“Photoacoustic Measurement of Electron Injection Efficiencies and Energies from Excited Sensitizer Dyes into Nanocrystalline TiO2 Films”
    C. Serpa, J. Schabauer, A. P. Piedade, C. J. P. Monteiro, M. M. Pereira, P. Douglas, H. D. Burrows, L. G. Arnaut, J. Am. Chem. Soc, 130 (2008) 8876-8877.

“Electron Transfers in Supercritical CO2. Ultra-Exothermic Charge Recombinations at the End of the ‘Inverted Region’”
    C. Serpa, P. J. S. Gomes, L. G. Arnaut, S. J. Formosinho, J. Seixas de Melo, J. Pina. Chem. Eur. J., 12 (2006) 5014-5023.

“Absolute Rate Calculations for Atom Abstractions by Radicals. Energetic, Structural and Electronic Factors”
    L. G. Arnaut, A. A. C. C. Pais, S. J. Formosinho, M. Barroso, J. Am. Chem. Soc., 125 (2003) 5236-5246.

“Heavy-atom effects on metalloporphyrins and polyhalogenated porphyrins”
M. E. Azenha, A. C. Serra, M. Pineiro, M. M. Pereira, J. Seixas de Melo, L. G. Arnaut, S. J. Formosinho, A. M. d’A. Rocha Gonsalves., Chem. Phys., 280 (2002) 177-190.

“Photoacoustic Measurements of Porphyrin Triplet State Quantum Yields and Singlet Oxygen Efficiencies”
    M. Pineiro, A. L. Carvalho, M. M. Pereira, A. M.d’A. Rocha Gonsalves, L. G. Arnaut, S. J. Formosinho, Chem. Eur. J., 4 (1998) 2299-2307.

“A Critical Assessment of Classical and Semi-Classical Models for Electron Transfer Reactions in Solution”
S. J. Formosinho, L. G. Arnaut, R. Fausto, Prog. Reaction Kinetics, 23 (1998) 1-90.

"Excited-State Proton Transfer Reactions. II. Intramolecular Reactions"
    S. J. Formosinho, L. G. Arnaut, J. Photochem. Photobiol. A: Chem., 75 (1993) 21-48.

"Excited-State Proton Transfer Reactions. I. Fundamentals and Intermolecular Reactions"
    L. G. Arnaut, S. J. Formosinho, J. Photochem. Photobiol. A: Chem., 75 (1993) 1-20.

Recent Advances in Photoacoustic Calorimetry: Theoretical Basis and Improvements in Experimental Design"
    L. G. Arnaut, R. A. Caldwell, J. E. Elbert, L. A. Melton, Rev. Sci. Instruments, 63 (1992) 5381-89.


History

The origin of the Photonics and Reactivity laboratory can be traced back to 1973 when Sebastião Formosinho returned to the University of Coimbra after a PhD with Lord George Porter at the Royal Institution, in London. Formosinho had the first pulsed lased installed at the Chemistry Department and founded the group of Photochemistry. Luis Arnaut was a PhD student of Sebastião Formosinho from 1984 through 1988 and after a post-doc with Richard Caldwell at the University of Texas at Dallas, returned to Coimbra in 1989 as Assistant Professor to work in the Photochemistry group. Sebastião Formosinho retired in 2013 and the Photochemistry group originated the Structure, Energy and Reactivity Group and the Macromoleculles, Colloids and Photochemistry Group of the Coimbra Chemistry Centre.