Periodic Reporting for period 1 - NuCapCure (Development of innovative proton and neutron therapies with high cancer specificity by 'hijacking' the intracellular chemistry of haem biosynthesis.)
Berichtszeitraum: 2024-02-01 bis 2025-01-31
Glioblastoma multiforme (GBM), a deadly brain cancer, remains incurable due to its deep location and resistance to conventional therapies like photodynamic therapy (limited by light penetration) and neutron-based Capture Therapies (challenged by tumor specificity). The NuCapCure project introduces two groundbreaking approaches:
1. NuCapCure Proton combines proton radiotherapy’s precision with protondynamic therapy (activating photosensitizers via protons) and proton capture therapy (generating three alpha particles per proton interaction) for localized, multi-mechanistic tumor destruction.
2. NuCapCure Neutron enhances the efficacy of conventional neutron capture therapiesby integrating neutron-activated photosensitizers (from the FRINGE project) to improve tumor targeting and efficacy.
Both strategies exploit engineered compounds using intracellular biosynthesis to produce custom therapeutic agents in situ, aiming to overcome drug delivery barriers. The project unites experts across proton/neutron physics, synthetic chemistry, radiobiology, and oncology to pioneer targeted, curative treatments for GBM and other intractable cancers.
The overarching goal of NuCapCure is the development of two radical, multimodal anticancer treatments, very specific to GBM, via the formation of bespoke PSs using intracellular biochemistry: A treatment combining proton radiotherapy, proton capture therapy and proton-induced PS activation.
The specific project objectives are:
• Design, development, validation and optimisation of NuCapCure bespoke prodrugs for the intracellular production of modified PSs.
• Initial photophysical characterization and conventional PDT studies on the various NuCapCure compounds in cell cultures (WP2).
• In-vitro validation and optimisation of the NuCapCure treatments in 2D and 3D GBM cell cultures. Selection of the best in-vitro performing PSs for subsequent in-vivo studies (WP3).
• In-vivo validation of NuCapCure efficacy, on GBM preclinical tumour models (WP4).
If successful NuCapCure could provide:
• A significant clinical advancement by offering curative solutions to currently incurable cancer indications
• New avenues in using cells for bespoke intracellular synthesis
• A boost to the European and international medical business sector by creating new therapies and hence new employment and marketing opportunities.
1. NuCapCure Proton combines proton radiotherapy’s precision with protondynamic therapy (activating photosensitizers via protons) and proton capture therapy (generating three alpha particles per proton interaction) for localized, multi-mechanistic tumor destruction.
2. NuCapCure Neutron enhances the efficacy of conventional neutron capture therapiesby integrating neutron-activated photosensitizers (from the FRINGE project) to improve tumor targeting and efficacy.
Both strategies exploit engineered compounds using intracellular biosynthesis to produce custom therapeutic agents in situ, aiming to overcome drug delivery barriers. The project unites experts across proton/neutron physics, synthetic chemistry, radiobiology, and oncology to pioneer targeted, curative treatments for GBM and other intractable cancers.
The overarching goal of NuCapCure is the development of two radical, multimodal anticancer treatments, very specific to GBM, via the formation of bespoke PSs using intracellular biochemistry: A treatment combining proton radiotherapy, proton capture therapy and proton-induced PS activation.
The specific project objectives are:
• Design, development, validation and optimisation of NuCapCure bespoke prodrugs for the intracellular production of modified PSs.
• Initial photophysical characterization and conventional PDT studies on the various NuCapCure compounds in cell cultures (WP2).
• In-vitro validation and optimisation of the NuCapCure treatments in 2D and 3D GBM cell cultures. Selection of the best in-vitro performing PSs for subsequent in-vivo studies (WP3).
• In-vivo validation of NuCapCure efficacy, on GBM preclinical tumour models (WP4).
If successful NuCapCure could provide:
• A significant clinical advancement by offering curative solutions to currently incurable cancer indications
• New avenues in using cells for bespoke intracellular synthesis
• A boost to the European and international medical business sector by creating new therapies and hence new employment and marketing opportunities.
The project kicked off in February 2024. In the first reporting period the big focus was placed on the synthesis of the bespoke chemicals that are required for NuCapCure therapies. As of course anticipated paper-chemistry was completely different to real-time chemical synthesis, several challenges were faced but within this period the first NuCapCure compound was released for analysis. The analysis performed showed that this compound had high cell toxicity at relatively low concentrations (for our purpose) but still gave some interesting results which the consortium is currently analyzing. To assist the NuCapCure effort, a scientist from NCSRD with expertise in molecular docking on enzymes and function in silico, has also joined the NCSRD team and can potentially guide our steps with the compound synthesis.
The compound was evaluated for its spectroscopic properties, its chemical toxicity and the result of its application was evaluated by HPLC on cell lysates. The progress of the chemistry and compound validation efforts will be continuously assessed in the next reporting period.
In the remit of WP3, UiO and OUS conducted experiments to characterize the dosimetry of the experimental setup at the Oslo Cyclotron Laboratory (OCL) using various cell dishes and to initiate the study of proton cytotoxicity on the U87 glioblastoma (GBM) cell line. This work will lay the foundations for the future work on cells, and is aimed to determine the Bragg peak of protons produced at OCL, so the in vitro experiments can be performed at a range around that. This experimental work was guided by both in house simulations using Geant-4 and NCSRD sim
As part of the preparations of the proton experiments, UMCG physicists have performed computer simulations of the dose distribution given by the protons as well as the dose deposited by the alpha particles produced in the reaction of protons with boron nuclei. With the help of these simulations the proton irradiation can be designed. First tests with high current proton beams for FLASH irradiations have been performed by PARTREC operators. As a part of preparatory work, the IMPACT infrastructure has been realized and preparations for commissioning the equipment have started by technicians from PARTREC.
At CVR, calculation analysis using the particle transport code MCNP was carried out to simulate the need for neutron beam modification. The neutron port should have a flux of 4.8e+8 thermal neutrons, representing 98.4% of the total neutron population in the channel. In accordance with these preliminary calculations, filter components of silicon, sapphire and bismuth were ordered. Aluminum holders and manipulators were designed and fabricated to house the crystals inside the tube of the neutron beam to form thermal neutron filters. The filters were mounted into the tube of the HK5 channel to form a basic irradiation setup. In the next months prior to M20 the ordering of biological shielding material and its installation around the exit of the HK5 beamline is expected.
The compound was evaluated for its spectroscopic properties, its chemical toxicity and the result of its application was evaluated by HPLC on cell lysates. The progress of the chemistry and compound validation efforts will be continuously assessed in the next reporting period.
In the remit of WP3, UiO and OUS conducted experiments to characterize the dosimetry of the experimental setup at the Oslo Cyclotron Laboratory (OCL) using various cell dishes and to initiate the study of proton cytotoxicity on the U87 glioblastoma (GBM) cell line. This work will lay the foundations for the future work on cells, and is aimed to determine the Bragg peak of protons produced at OCL, so the in vitro experiments can be performed at a range around that. This experimental work was guided by both in house simulations using Geant-4 and NCSRD sim
As part of the preparations of the proton experiments, UMCG physicists have performed computer simulations of the dose distribution given by the protons as well as the dose deposited by the alpha particles produced in the reaction of protons with boron nuclei. With the help of these simulations the proton irradiation can be designed. First tests with high current proton beams for FLASH irradiations have been performed by PARTREC operators. As a part of preparatory work, the IMPACT infrastructure has been realized and preparations for commissioning the equipment have started by technicians from PARTREC.
At CVR, calculation analysis using the particle transport code MCNP was carried out to simulate the need for neutron beam modification. The neutron port should have a flux of 4.8e+8 thermal neutrons, representing 98.4% of the total neutron population in the channel. In accordance with these preliminary calculations, filter components of silicon, sapphire and bismuth were ordered. Aluminum holders and manipulators were designed and fabricated to house the crystals inside the tube of the neutron beam to form thermal neutron filters. The filters were mounted into the tube of the HK5 channel to form a basic irradiation setup. In the next months prior to M20 the ordering of biological shielding material and its installation around the exit of the HK5 beamline is expected.
Even though it is early in the project there are some results already. These include a new chemical entity according to the specifications of NuCapCure. This compound, which is unique in its kind, was tested for its compatibility with our proposed technology and was found to be toxic to cells at quite a low concentration. Nevertheless, it was found to produce some interesting results which we are currently analyzing. We believe we are in the right way, but it is going to require some time to identify the right compounds. Meanwhile we are studying its intriguing behaviour in an effort to understand better what is happening in our system. In specific we have seen the formation of a new spectroscopically active species, and we have seen that use of our compound mixed with the natural substrate, produce more PS than the natural substrate on its own, even though the compound on itself, does not produce any PS.
The sooner we will understand and harness our system the sooner we will be able to put our technology to work and produce some results. We were expecting the chemistry to be challenging, but as the work proceeds and after the first compound, everything is easier for the production of several compounds.
The sooner we will understand and harness our system the sooner we will be able to put our technology to work and produce some results. We were expecting the chemistry to be challenging, but as the work proceeds and after the first compound, everything is easier for the production of several compounds.