TheraGlio - developing theranostics for gliomas.

The idea of TheraGlio is to develop a multimodal imaging system for Theranostics (therapy+diagnosis) of patients bearing malignant glioma, the most common primary brain tumour. This technology will avail of new generation Microbubbles (MBs) that can simultaneously act as drug delivery system and contrast agent for Magnetic Resonance Imaging, intra-operative Contrast-Enhanced Ultrasound and intra-operative fluorescence microscopic. This novel imaging system will provide multimodal image guidance during tumour resection with the final goal of prolonging patients' survival, as a result of a safer and larger tumour resection and tailored delivery of specific chemotherapeutic molecules.

| 1 | Malignant gliomas (MG) constitute at least 35% of all primary brain tumours and are the 3rd leading cause of death from cancer in people from 15 to 34 years of age. Surgery plays a major role in the treatment of MG, since the surgical extent of resection is clearly associated with improved patient survival [Sanai & Berger (2008)]. Unfortunately, a complete surgical removal of these tumours is achieved in less than 20% of cases [Albert, 1994; Kowalczuk (1997)] also because of technical difficulties in identifying the tumour borders during surgery [Shrieve et al (1999); Wood (1988)]. Intra-operative fluorescence and ultrasound (US) guidance are functional to improve tumour resection, however both techniques have several limitations. Therefore, improving intra-operative US image quality with an appropriate contrast agent, and combining it with intraoperative fluorescence and pre-operative Magnetic Resonance Imaging (MRI) is highly desirable in order to achieve a better intraoperative discrimination of the tumour margins and safely maximize resection. Microbubbles (MBs) are a well-established contrast agent for US imaging. Moreover poly (vinyl alcohol)-based MBs already allow to support three different imaging modalities - US, MRI and single-photon emission computer tomography. As such they represent the perfect candidate for improving pre- and intra-operative MG multimodality imaging.

| 2 | The specific objectives of the project are:

  1. Designing a new neurosurgical navigation system to simultaneously acquire intra- operative CEUS 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 and clinical-grade GMP certified 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, CEUS and fluorescence microscopic visualization.
  4. Development of multifunctional biodegradable MBs equipped with drug-loaded-nanoparticles functioning as drug delivery platform.
  5. Clinical assessment of feasibility, toxicity, and efficacy of multimodal modified lipid-stabilized MBs for real-time MR/CEUS/fluorescence.

| 3 | TheraGlio objectives will be achieved by through the following key steps:

  1. Designing a new neurosurgical navigation system specifically dedicated to the joint acquisition of intraoperative US, microscopic images and their real-time fusion with pre-operative MRI scans.
  2. Manufacturing, optimization of multimodal lipidic MBs.
  3. Manufacturing and physical characterization of bio-inert or biodegradable polymeric, multifunctional MBs.
  4. Development of multifunctional nanoparticles-containing MBs as drug delivery.
  5. Safety assessment studies in big animal models.
  6. In vivo characterization of MBs in a glioma animal model.
  7. Preliminary clinical experiments in humans.

| 4 | TheraGlio will likely provide a formidable device for the integration of MR imaging, US imaging, and optical intra-operative visualization, down to the molecular level of malignant glioma. It will also 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 diagnosis and therapy delivery in malignant glioma 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. In fact malignant gliomas are not curable because radical tumour resection is not achievable in most 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 malignant glioma, also provides the tool 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 malignant glioma 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 neoplasic conditions where surgical radicality and better drug delivery is important.