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Traversing the Experimental and Computational Landscapes: Wielding, Refining, and Forging the Toolkit for Rational Design of Partially Fluorescent Near-Infrared BODIPY Photosensitizers for Image-Guided Photodynamic Therapy
No full textThe advances in healthcare of the past two centuries have drastically increased
our average life expectancy by mitigating the prevalence and lethality of
numerous conditions. In this progression, the challenge for maintaining our health
continuously shifts to conditions that are harder to cure. Herein cancer stands
undoubtedly as the final frontier, taking the lives of an estimated 10 million people
in 2020 and already having overtaken cardiovascular disorders as the leading cause
of death in several high-income countries. Although the survivability of cancer has
tremendously progressed through the reduction of risk factors, early diagnosis,
and improvements in well-established therapies such as surgery, radiotherapy,
and chemotherapy, the recent decades have been characterized by the rise of
alternative techniques like immunotherapy and photodynamic therapy.
The latter example is a light-based method that has been approved by the United
States Food and Drug Administration since 1995 and which is currently applied
in multiple countries for the treatment of a broad set of cancers. Photodynamic
therapy operates via a compound, commonly known as a photosensitizer, that
is capable of absorbing light and passing the therefrom obtained energy over to
oxygen molecules. The resulting excited, or singlet, oxygen is very reactive and
will immediately damage its close surroundings. This destructive effect can be
applied very specifically to cancer cells by letting the administered photosensitizer
preferentially accumulate inside tumor tissues and then activating it with a targeted
light irradiation, thereby leaving healthy tissue unharmed.
Despite carrying great potential, contemporary photodynamic therapy is held back
by the mediocre functioning of the currently available commercial photosensitizers.
Their composition can be ill-defined, they may have a poor distribution throughout
the body and clear very slowly from it, they use light that is easily scattered or
absorbed by biological tissues, and their lack of fluorescence does not allow their
location to be traced for diagnostic purposes. Thus, ideally, the photosensitizer
is a pure and partially fluorescent compound that possesses a powerful singlet
oxygen generation capacity and a strong absorption of red to near-infrared
light, as this penetrates the deepest into the tissue. This thesis constitutes one
of the many efforts that have been devoted towards the creation of better
photosensitizers, thereby taking a holistic approach by not only focusing on the
substances themselves, but also on the tools by which they are designed and
analyzed. The first part of the thesis is dedicated to those tools which make use of theoretical
quantum chemical models to calculate a broad scope of molecular properties that
are in many cases difficult to determine experimentally. Predicting these properties
is very useful for the preliminary screening of potential photosensitizers and for
revealing the intricate mechanisms governing their observed behavior. However,
the method by which this is done always provides an approximation of reality
and this is only of any value if it is sufficiently correct and if the amount of
computational resources required for it is reasonable. Density functional theory,
and its time-dependent form, is a technique with a comparatively great accuracy
for its cost, giving it its place as the de facto standard for experiment-adjacent
research. Yet, its performance is strongly dependent on the systems that are
being evaluated and the choice of its exchange-correlation functional. In order
to find an optimal procedure for investigating the class of compounds covered in
this thesis, an assessment of the consistency and accuracy of several parameters
and exchange-correlation functionals was carried out, thereby comparing to
experimental data of such compounds and to results obtained from a higher
level method, i.e., SCS-riCC2. In another chapter, a widely used measure for the
length of charge displacement during a molecular excitation was reconfigured to
a symmetry-independent form. That way, the charge transfer characteristics of
molecules and excitations can be analyzed regardless of their shape.
In the second part, these newly refined tools were utilized to successfully develop
partially fluorescent near-infrared-active photosensitizers. One employed approach
was to introduce photosensitization capacities to the strongly near-infrared
fluorescent pyrrolopyrrole aza-BODIPY dye. This was done by attaching an electron
rich structure to the electron poor dye, creating a donor-acceptor system capable
of forming charge transfer excited states that can serve as an intermediate for
the molecule to reach the state from which it generates singlet oxygen. The
same results can be achieved without a charge transfer state by twisting the
molecular geometry. The other approach, covered in the final chapter, was to
shift the absorption of a partially fluorescent twisted BODIPY photosensitizer to
the near-infrared, thereby also attempting to induce extra phototoxic power by
going for a donor-acceptor design. This second idea proved crucial for the success
of the project, as the red shift compromised the delicate twist-based mechanism.
Nevertheless, high-performing photosensitizers were obtained throughout the
thesis and with the computational insights gained during the effort, many new
promising photosensitizers are within reach
Investigating XC-functionals towards describing experimentally relevant excited-state properties of NIR-BODIPY derivatives
No full textThe predictive and analytical power of time-dependent density functional theory (TD-DFT) has been instrumental in the design and mechanistic understanding of numerous organic chromophores. Yet, the widely popular boron-dipyrromethene (BODIPY) dye class suffers from notorious TD-DFT accuracy issues, undermining the serviceability of the technique. Highly correlated wave function approaches are much better at reproducing photophysical properties but become computationally unviable when making the push towards larger near-infrared (NIR) active structures. In an effort to find the protocol most capable of helping experimentalists design and analyze novel NIR BODIPYs, we have benchmarked 11 global or range-separated hybrid exchange-correlation functionals (XCFs) with different amounts of Hartree-Fock exchange. By relating both transition energies and oscillator strengths, first through a set of resolution-of-the-identity second-order coupled cluster (riCC2) calculations and then directly to experimental data, it is revealed that M06-2X and M06-HF behave most consistently for singlet and triplet excitations. To optimize accuracy across states, we recommend a hybrid approach where singlets are obtained through full TD-DFT and triplets are treated using the Tamm-Dancoff approximation.</p
Earth Mover’s Charge Transfer Distance:A General and Robust Approach for Describing Excited State Locality
No full textA novel approach for assessing the extent of electron displacement in optical transitions is proposed by implementing the Earth Mover’s Distance (EMD) method, which quantifies the spatial dissimilarity between ground and excited state electron density distributions. In contrast to previous descriptors, this index provides a representative and intuitively understandable distance under a robust and computationally efficient scheme for all possible forms of locality, even in the most difficult to dissect topological cases. The theoretical differences among the existing indices and our method are first illustrated with the help of a simplified model system, followed by a benchmarking of several partial atomic charge models using experimentally relevant push-pull compounds with diverse symmetries. These same molecules are finally employed to further demonstrate the principal advantages of the EMD index and its capabilities in rationalizing charge transfer phenomena.</p
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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