Over the past two centuries, advances in healthcare have significantly extended life expectancy by reducing the impact of many diseases. As this progress continues, attention shifts toward more complex illnesses, with cancer emerging as the foremost challenge. Photodynamic therapy (PDT) is a light-activated cancer treatment approved in 1995 that offers a targeted approach by using photosensitizers (PSs) — compounds that, upon light activation, generate reactive singlet oxygen to selectively damage tumor tissue.
However, current commercial PSs suffer from several drawbacks: ill-defined composition, poor accumulation in tumors and slow clearance, limited application depths, and insufficient fluorescence for diagnostic imaging. This thesis addresses these limitations by pursuing the development of efficient and partially fluorescent PSs that absorb strongly in the red to near-infrared (NIR) range.
The first part of the work focuses on computational tools based on quantum chemistry, particularly density functional theory, to predict molecular properties relevant to PDT. These methods are benchmarked and refined to ensure accurate and efficient screening of candidate compounds. Additionally, a commonly used metric for quantifying charge transfer distance in excited states is reformulated to be independent of molecular symmetry, allowing broader and more robust applicability.
In the second part, these tools guide the design of novel PSs. One strategy involves modifying pyrrolopyrrole aza-BODIPY dyes into donor–acceptor structures to enable singlet oxygen generation via spin–orbit charge transfer intersystem crossing (SOCT-ISC). Another approach focuses on a twisted BODIPY compound that achieves photosensitization by facilitating ISC through a distortion of the symmetry. This PS is tuned to absorb NIR light and, in some cases, leverage the SOCT-ISC mechanism. Overall, these efforts did not only yield promising PSs but also provided computational insights to accelerate future developments in the field.
