Periodic Reporting for period 4 - INFRADYNAMICS (Overcoming the Barriers of Brain Cancer Treatment: Targeted and Fully NIR Absorbing Photodynamic Therapy Agents with Extremely Low Molecular Weights and Controlled Lipophilicity)
Période du rapport: 2024-05-01 au 2025-10-31
Brain cancers, particularly glioblastoma (GBM), remain among the most lethal malignancies due to limited surgical options, the blood–brain barrier (BBB), and the lack of truly targeted therapies. Photodynamic therapy (PDT) is a minimally invasive, spatially controlled treatment modality in which a photosensitizer (PS) is activated by light to generate reactive oxygen species (ROS) that induce localized cell death. Despite its clinical promise, Photodynamic therapy (PDT) has had limited success in treating brain cancer for several practical reasons. First, only a small number of PDT drugs can be activated by light that penetrates deeply enough into brain tissue. Second, many existing agents do not selectively accumulate or activate in tumors. Finally, most photosensitizers are either too large or have inappropriate lipophilicity, preventing them from crossing the BBB and reaching the tumor in adequate amounts.
The INFRADYNAMICS (InDy) project addressed these challenges by shifting the focus from incremental improvements to rational molecular design. The project aimed to develop small, near-infrared (NIR)-absorbing PSs with carefully balanced chemical properties, enabling efficient light activation, generation of reactive oxygen species, and improved access to brain tumors. This approach laid the groundwork for early, targeted, light-based treatment strategies for brain cancers.
The overall objectives of InDy were:
(1) to demonstrate that strong red/NIR absorption can be achieved without large molecular weights through minimal, rational modifications of simple fluorophore scaffolds;
(2) to convert these fluorophores into efficient PSs using synthetically viable heavy-atom strategies while controlling lipophilicity; and
(3) to achieve tumor selectivity via targeted or activatable molecular “handles” responsive to brain-cancer biology, followed by systematic photophysical and biological validation.
By the end of the project, InDy had matured from a high-risk hypothesis into a validated molecular design platform. The project delivered multiple first-in-class PSs, demonstrated selective and potent PDT activity against GBM and neuroblastoma, and established enzyme-responsive PDT paradigms tailored to brain cancer. Collectively, these outcomes validate the core premise of InDy and provide durable foundations for future preclinical development and translation.
The INFRADYNAMICS (InDy) project addressed these challenges by shifting the focus from incremental improvements to rational molecular design. The project aimed to develop small, near-infrared (NIR)-absorbing PSs with carefully balanced chemical properties, enabling efficient light activation, generation of reactive oxygen species, and improved access to brain tumors. This approach laid the groundwork for early, targeted, light-based treatment strategies for brain cancers.
The overall objectives of InDy were:
(1) to demonstrate that strong red/NIR absorption can be achieved without large molecular weights through minimal, rational modifications of simple fluorophore scaffolds;
(2) to convert these fluorophores into efficient PSs using synthetically viable heavy-atom strategies while controlling lipophilicity; and
(3) to achieve tumor selectivity via targeted or activatable molecular “handles” responsive to brain-cancer biology, followed by systematic photophysical and biological validation.
By the end of the project, InDy had matured from a high-risk hypothesis into a validated molecular design platform. The project delivered multiple first-in-class PSs, demonstrated selective and potent PDT activity against GBM and neuroblastoma, and established enzyme-responsive PDT paradigms tailored to brain cancer. Collectively, these outcomes validate the core premise of InDy and provide durable foundations for future preclinical development and translation.
From its inception, InDy pursued a high-risk, high-gain research strategy integrating molecular design, synthesis, photophysical characterization, and biological evaluation. Early work focused on establishing the project's technical foundations, including computationally guided design, new synthetic routes for low-molecular-weight fluorophores, and experimental workflows that link chemical synthesis to photophysical and cellular testing. Initial benchmark compounds validated the feasibility of converting simple fluorophores into effective PSs via minimal structural modifications.
As the project progressed, efforts shifted toward expanding chemical diversity and addressing more demanding objectives, such as achieving NIR absorption in water while maintaining low molecular weight and biological activity against GBM. This phase required extensive synthetic development and resolution of long-standing chemical bottlenecks. In parallel, an integrated biological evaluation pipeline was established, enabling systematic assessment of phototoxicity, selectivity, intracellular behavior, and mechanism of action, and allowing rapid iteration between molecular design and biological outcome.
By the end of the project, InDy had delivered several major scientific breakthroughs. Most notably, the project demonstrated that low-molecular-weight photosensitizers can combine NIR absorption in water with robust and selective activity against GBM. The discovery of such agents was not predictable at the design stage and represents a clear advance beyond the existing state of the art Equally important, the project delivered enabling synthetic methodologies that overcame long-standing barriers in the field and allowed access to previously inaccessible molecular families. These advances were consolidated into a unified InDy design platform. InDy also established entirely new enzyme-responsive PDT paradigms for brain cancers. For the first time, B-galactosidase, monoamine oxidase, and leucine aminopeptidase were shown to function as practical biological triggers for selective light-based brain cancer therapy. These systems combine diagnostic and therapeutic functions and introduce new levels of selectivity and control.
InDy also made a substantial contribution to training and capacity building, involving PhD, MSc, postdoctoral, and undergraduate researchers, and resulting in multiple theses, conference presentations, and high-impact publications. Results were disseminated through peer-reviewed articles in leading journals (i.e. JACS Au), invited seminars, and international conferences (i.e. ACS Meeting), reaching audiences across chemistry, photophysics, and cancer biology. From an exploitation perspective, the project established a protected design platform supported by a European patent, providing a clear pathway for continued preclinical development and translational research.
As the project progressed, efforts shifted toward expanding chemical diversity and addressing more demanding objectives, such as achieving NIR absorption in water while maintaining low molecular weight and biological activity against GBM. This phase required extensive synthetic development and resolution of long-standing chemical bottlenecks. In parallel, an integrated biological evaluation pipeline was established, enabling systematic assessment of phototoxicity, selectivity, intracellular behavior, and mechanism of action, and allowing rapid iteration between molecular design and biological outcome.
By the end of the project, InDy had delivered several major scientific breakthroughs. Most notably, the project demonstrated that low-molecular-weight photosensitizers can combine NIR absorption in water with robust and selective activity against GBM. The discovery of such agents was not predictable at the design stage and represents a clear advance beyond the existing state of the art Equally important, the project delivered enabling synthetic methodologies that overcame long-standing barriers in the field and allowed access to previously inaccessible molecular families. These advances were consolidated into a unified InDy design platform. InDy also established entirely new enzyme-responsive PDT paradigms for brain cancers. For the first time, B-galactosidase, monoamine oxidase, and leucine aminopeptidase were shown to function as practical biological triggers for selective light-based brain cancer therapy. These systems combine diagnostic and therapeutic functions and introduce new levels of selectivity and control.
InDy also made a substantial contribution to training and capacity building, involving PhD, MSc, postdoctoral, and undergraduate researchers, and resulting in multiple theses, conference presentations, and high-impact publications. Results were disseminated through peer-reviewed articles in leading journals (i.e. JACS Au), invited seminars, and international conferences (i.e. ACS Meeting), reaching audiences across chemistry, photophysics, and cancer biology. From an exploitation perspective, the project established a protected design platform supported by a European patent, providing a clear pathway for continued preclinical development and translational research.
InDy delivered advances that clearly go beyond the state of the art in PDT for brain cancers. A central breakthrough was the discovery of a low-molecular-weight photosensitizer (NSeAze, <360 g/mol) that combines NIR absorption in water with exceptional light-induced toxicity toward GBM cells while remaining largely inactive in the dark. Before InDy, no PS had been reported that simultaneously achieved NIR absorption in aqueous media, BBB-compatible molecular weight, and nanomolar-level potency in GBM models. Crucially, this breakthrough arose from a minimalist molecular design strategy. While the original goal was to examine whether subtle changes would influence intracellular localization, the resulting biological outcome was far more striking. This finding revealed that even very subtle structural changes can dramatically alter biological activity and treatment efficiency. It represents a genuine conceptual advance and validates the core InDy principle: that carefully controlled modifications to a simple molecular scaffold can simultaneously tune light absorption, reactive oxygen species generation, and biological response, yielding highly efficient PDT agents for brain cancers.
InDy also established entirely new enzyme-responsive PDT paradigms for brain cancers. For the first time, B-galactosidase, monoamine oxidase, and leucine aminopeptidase were shown to be practical biological triggers for selective light-based cancer therapy in glioblastoma and neuroblastoma. These systems enable activity-based activation and dual Type I/Type II phototoxic mechanisms, which are particularly relevant for hypoxic tumors such as GBM.
Finally, InDy achieved lasting impact through the development of enabling synthetic methodologies and a unified design platform, now protected by a European patent. These advances overcame long-standing chemical barriers and unlocked access to previously inaccessible PS families. The molecular libraries, synthetic tools, and biological insights generated during the project provide a robust and exploitable foundation for continued innovation and future clinical translation of selective PDT strategies for brain cancers.
InDy also established entirely new enzyme-responsive PDT paradigms for brain cancers. For the first time, B-galactosidase, monoamine oxidase, and leucine aminopeptidase were shown to be practical biological triggers for selective light-based cancer therapy in glioblastoma and neuroblastoma. These systems enable activity-based activation and dual Type I/Type II phototoxic mechanisms, which are particularly relevant for hypoxic tumors such as GBM.
Finally, InDy achieved lasting impact through the development of enabling synthetic methodologies and a unified design platform, now protected by a European patent. These advances overcame long-standing chemical barriers and unlocked access to previously inaccessible PS families. The molecular libraries, synthetic tools, and biological insights generated during the project provide a robust and exploitable foundation for continued innovation and future clinical translation of selective PDT strategies for brain cancers.