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Periodic Report Summary 3 - THERAGLIO (Microbubble driven multimodal imaging and theranostics for gliomas)

Project Context and Objectives:
TheraGlio aims at developing combined imaging technologies for diagnostic and tailored therapeutic interventions for patients bearing MGs. This will be carried out by creating a novel multimodal imaging system, which will employ new generation MBs that can simultaneously act as contrast agent for Magnetic Resonance Imaging (MRI), intra-operative US Imaging, including Contrast-Enhanced US (CEUS), and intra-operative fluorescence-guided microscopic resection of MG. Moreover, newly generated MBs will be loaded with specific targeting molecules and chemotherapeutics for localized release. The specific objectives of the project will be:
1) Designing a new neurosurgical navigation system to simultaneously acquire intra- operative US and operative-microscope images, and match them with the pre-operative MRI scans in real-time.
2) Manufacturing and preclinical assessment of stability, toxicity and efficacy of lab-scale multimodal lipidic MBs as an intra-operative neuro-navigation tool.
3) Manufacturing and physical characterization of polymeric (bio-inert or biodegradable), multifunctional MBs, which will be functionalized for MRI, US and fluorescence microscopic visualization.
4) Development of multifunctional drug-loaded-nanoparticle equipped biodegradable MBs as drug delivery platform.
5) Clinical evaluation of feasibility, usability and precision of the multimodal platform using commercially available MBs (SonoVue) in combination with ICG (both EMA-approved) for real-time MR/US image/fluorescence guided surgery using an integrated neuronavigation platform in recurrent GBMs; proof of principle test to validate the functionality of the new platform in vivo.

Project Results:
WP1 Advanced image-guided neurosurgical navigation platform development
Achievements:
• Development of new advanced image guided neurosurgical platform based on Ultrasound and image fusion tool which is actually in use by clinical partners P1 FINCB and P3 TASMC (Task 1.7) according to a specific protocol and upon IRB approval. In details;
o Intraoperative surgery planning to improve both diagnostic decision making and planning of intervention by a manual, semi-automatic or automatic procedure;
o 3D automatic tuning of pre-operative MR imaging and real -time US by advanced image registration techniques;
o Advanced brain-shift management during surgery by a continuous and automatic adjustment of the system by following brain deformation throughout the whole surgical procedure. The developed solution is allow to improve the actual state of art about the brain shift issue during surgery; automatic pre-operative MR adjustment according to the 3D US (including CESU) during surgery
o Availability of specific tools namely pre-operative stylus for craniotomy and surgical planning, intra-operative diagnostic decision making supported by US tools, like CEUS and Doppler, remote (tablet) keyboard to improve system usability, spatial tracking of US probes and of surgical optical microscope for integrated use of project platform during surgery by exploiting the same EM tracking system used by the US system;
o Realization of a US system and microscope integration. Technical integration and data exchange between all the components developed, allowing to gather data on the positions and orientation of the microscope and US probe, and consequently of the data acquired from both imaging systems.
o Microscope stereo image calibration, that needs to be performed only once after having placed the sensor holder, and is carried out acquiring with the microscope and appropriately processing a video of a calibration checkerboard.
o Microscope stereo reconstruction, allowing for the 3D reconstruction of the scene viewed through the microscope opticals, and its later fusion together with other 3D data, spatially referenced in the same coordinates system.
o Combined data visualization during surgery: US, MRI data and Optical microscope 3D reconstructed video integration in a single, VR-like visualization panel, either on a standard monitor or on 3D monitors;
• Preliminary evaluation of the platform in order to collect a feedback about effectiveness, usability, reliability, ergonomicity etc.

WP2 Production, physicochemical and in vitro characterization of the modified lipid-stabilized
commercially available MBs
Achievements:
• Appropriate characterization protocols have been also developed.
• Implementation of production process and obtaining of lipidic MBs under GMP-like conditions.

WP3 Development and characterization of multifunctional polymer-stabilized MBs
Achievements:
• Engineering PVA-based MBs with multifunctional surface molecules (Physical-Chemical and in vitro biological assessment of PVA-based MBs)
• Production of targeted drug-loaded SPIONs for drug delivery and MRI tracking (Physical-Chemical and in vitro biological assessment)
• Engineering biodegradable MBs with multifunctional surface molecules (Physical-Chemical and in vitro biological assessment of biodegradable MBs)

WP4 Development and multifunctional nanoparticulated drug delivery system
Achievements:
The research work conducted in this period allowed us to:
• investigate alternative synthetic routes to render NPs Synthesis cheaper, greener, and even more scalable.
• select of a panel of surface functionalisations that are suitable for NP colloidal stability, MB crosslinking, drug loading and at the same time meet criteria for future synthesis scalability
• Establishment of synthetic procedure, functionalization and drug loading protocol
• Establishment of in vitro cell toxicity test for the evaluation of drug-loaded NPs efficacy

WP5 Assessment of toxicity and safety
Achievements:
• In vitro toxicity testing of lipidic MBs on endothelial, liver, neuronal and kidney cells
• In vitro testing of MBs as well as different targeting molecules regarding in vitro immunogenicity in human sera
• In vivo testing of immunotoxicity of lipid MBs in big animal pig model
WP6 In vivo functionality of the MBs in rat brain tumour models
Achievements
In view of the reported findings and under the conditions of this study, it may be concluded that:
• a single intravenous (IV) injection of any of the Test Items Naked Microbubbles (MB), MB-ICG, MB-RGD and MB-ICG-RGD at a dose level of 252 mg/kg is considered to be the no-observed-adverse-effect-level (NOAEL) for each Test Item. The 10-fold higher dose level of 2520 mg/kg of any of the Test Items was associated with adverse effects. Compliance with good laboratory practice.
• following a single intravenous (IV) administrations of the Test Items Microbubbles (MB)-ICG and MB-RGD -ICG to male Sprague-DawleyTM (SDTM) rats, the Test Items are present at the brain. It is likely that the Test Items are also distributed to other tissues, however because of the limitations of the imaging techniques, biodistribution to other organs cannot be proven.
WP7 Clinical Study Governance
Achievements
• Definition of the protocol and its implementation as an observational prospective, dual Centre, cohort trial.
• IRB approval has been obtained

WP8 Performance of the clinical study to evaluate the new integrated neuro-navigation platform

• Experiments on phantoms
• successful implementation and testing of the automatic calibration procedure and the significant improvements in the computational speed of the reconstruction algorithms allow online analysis.

WP9 Dissemination Exploitation
Achievements:
• 54 dissemination activities among oral presentations and posters
• 6 peer-reviewed publications

Potential Impact:
TheraGlio will contribute to the expected impacts listed in the work programme in relation to topic HEALTH.2013.1.2-1: Development of imaging technologies for therapeutic interventions in rare diseases as follows:
• The development of new and improved technologies for therapeutic interventions in groups or categories of rare diseases
The project is expected to develop and validate novel combined imaging technologies for personalized therapeutic interventions, for a rare form of human cancer, malignant glioma. TheraGlio will likely provide a device for the integration of MR imaging, US imaging, and optical intra-operative visualization, down to the molecular level of malignant brain tumours. It will support the proof of-principle of using MBs as a platform for targeted delivery of therapeutic molecules, which coupled with its properties as medical imaging agent will open an innovative approach for Theranostic (therapy+diagnosis) in MG treatment. This will potentially lead to a significant improvement in defining the tumour extension, understanding the disease biology, determining the functionality of the nearby normal brain tissue, and improving the patients’ overall survival (eventually, the most relevant clinical outcome parameter). In fact MG are not curable because radical tumor resection is not achievable in most of the cases; besides, even when this is feasible, still residual invading cells represent the culprit of recurrence. This is why the TheraGlio project, with its holistic approach, aiming at better visualizing (intraoperatively) and resecting MB, also provides the tool (engineered/modified MBs) to locally deliver an effective chemotherapic drug to those residual cells, expecting to contribute to a longer survival of patients when compared to the current context of extremely poor prognosis. Since a better tool to intraoperatively visualize MG is needed (along with the constant search for new ways of drug delivery to better molecular targets), the impact of the project would go far beyond the expected endpoints of the study. Implementation of project results would possibly improve the outcome of other severe neoplastic conditions where surgical radicality and better drug delivery is important.
• Facilitating the uptake of personalized medicine into clinical practice and support the competitiveness of Europe in this area
It has been shown that MG in general and Glioblastoma in particular represent a vast and heterogeneous pathological entity. In fact, it is well accepted that under the name GBM, we actually group many different tumours, which are characterized by distinct and peculiar genetic mutations that reflect varying level of biological aggressiveness. In this regard, it is clear that not all MB may benefit from the same drugs, since different molecular targets need to be reached in different subgroups of patients.
• The applications are expected to advance research in personalized medicine and have an impact in the relevant industry (in particular for SMEs).
TheraGlio will bring about key possible applications in the field of personalized medicine for the treatment of MG (see above). The achievement of those goals will lead to a most big impact in the relevant industries, particularly in regard to the SMEs that take part to the project. If we will manage to show that the integrated navigation system is effective in showing the lesion pre- and intraoperatively (allowing for larger tumour resection) the project achievements will be particularly relevant for SeroScience, MedCom, ESAOTE, Camelot, and Biopharma. Novel MBs, their related production methods and the local drug-delivery system through NPs, carried by MBs, will be interesting to FINCB, UNIROMA2, TASMC, NANOMOL and BIOPHARMA, as proven technological platforms to be exploded in cancer, degenerative and cardiovascular diseases treatment, consolidating or opening new business lines. Project partners will look for co-development and exploitation with other European SMEs and industries, fostering open innovation schemes.
• The projects will contribute to the International Rare Diseases Research Consortium (IRDiRC).

List of Websites:
http://www.theraglio.eu/project/

Reported by

FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA
Italy

Subjects

Life Sciences
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