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

Abstract

The 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.