Ultimately, VIBRANT will deliver β-cell specific, functionally optimized nanoconstructs and defined know-how for in vivo applications in non-human primates and humans with regard to quantification of BCM, imaging of pancreatic β-cell function and survival, and therapy in clinical trials. In summary, VIBRANT will be the consolidation of the developed nanoparticular agents, processes and associated methodology in view of comprehensive IP protection, and to prepare for its uptake after the project in concluding preclinical and clinical studies in follow-up cooperations with industrial partners from the pharmaceutical industry.
Overall, the nanoparticular concept of VIBRANT, as well as major instrumental biological models and essential imaging technologies are novel and exclusively established within the VIBRANT consortium. They represent a clear step beyond the state of the art and address the urgent need of further research in this area.
Scientific and technical quality
Concept and objectives
Diabetes results from an absolute or relative decline in pancreatic β-cell function and/or mass. In type 1 diabetes (T1DM), hyperglycaemia occurs when β-cells are selectively destroyed by an autoimmune process. In type 2 diabetes (T2DM), hyperglycaemia results when insulin secretion is inadequate to compensate for increased need of insulin caused by insulin resistance. Measurement of insulin secretion capacity is currently used as a surrogate measure of β-cell mass (BCM). Unfortunately, serum insulin or C-peptide concentrations provide only an imprecise reflection of BCM. Because the pancreas is a heterogeneous organ inaccessible to biopsy, and β-cell mass is dispersed as ~1 mio minute cell masses (islets) in the exocrine tissue there is currently no available reliable measure of BCM and thus it is currently not possible to distinguish reliably between anatomical versus functional defects of insulin secretion. The potential clinical value of non-invasive imaging the endocrine pancreas and thereby directly measuring β-cell mass is clear: Detecting β-cell loss in preclinical or early-onset type I diabetes may allow for changes in mass to be used as an end point marker in clinical trials designed to halt β-cell destruction. Similarly, anti-diabetic drugs such as Glucagon-like peptide agonists have been introduced in clinical practice in the treatment of Type 2 diabetes, and these novel drugs are believed from preclinical studies to stimulate β-cell regeneration. This could not be verified, since hitherto, no clinically established methodology for non-invasive in vivo imaging and quantification of β-cell mass exists.
Two anatomical features of the pancreas demand for technical solutions, far more advanced than those required for other imaging applications. First, as mentioned before, β-cells exist in tiny (100–300 µm in diameter) micro-organs, the islets of Langerhans, which are distributed throughout the exocrine pancreas. Each is too small to be spatially resolved by current non-invasive in vivo imaging methods. Second, the total β-cell mass, even in healthy humans, is so small (about 1 g) as to constitute only about 1–2% of the total pancreatic mass. Moreover, size dispersity is vast: Preliminary data from mice shows that less than 10% of the total number of β-cells could contribute to ~ 70 % of the total volume.
The principal goal of VIBRANT is the development of nano-technology-based systems for diabetes diagnosis and/or therapy.
Technical limitations of available imaging modalities such as positron emission tomography (PET), magnetic resonance imaging (MRI), and electron spin-resonance (ESR) pose particular challenges to imaging of β-cells. These limitations of currently used techniques include limited resolution (PET, ESR), sensitivity (MRI) and lack of contrast. Therefore, imaging technologies previously used for detecting focused objects as small as tumours of a few millimetres have to be optimized for detection and eventual quantification of the non-transformed or even reduced β-cell population more or less uniformly dispersed within the pancreas. This requires
- a contrast agent providing a stable and high signal intensity,
- a contrast agent that is highly specific to the cell type, but devoid of toxicity, and
- an imaging technology with the potential of paramount spatial resolution. For a more comprehensive knowledge about β-cell functionality with regard to proliferation and apoptosis, in order to eventually stall β-cell deterioration and induce increase of functional BCM, an agent will be desirable, which
- allows monitoring of functional aspects (viability status of the β-cell)
- holds the potential for a novel β-cell specific drug delivery system.
In order to address these objectives, VIBRANT will aim for a novel MRI contrast agent with hitherto unprecedented MRI sensitivity and spatial resolution power.In VIBRANT, a biocompatible, non-toxic polymeric nanocontainer containing a sensitive -optionally multimodal- reporter system or therapeutic agents was accomplished via highly reproducible microfluidic processes. The nanocapsules showed low unspecific binding, superior sensitivity and longitudinal signal stability in MRI and optical readouts. The outer surface of these nanocapsules was decorated with various recognition motifs for the in vivo targeting of the pancreatic β-cell. Substantial progress has been accomplished in in vivo imaging of functional β-cell mass and a novel ex vivo mesoscopic optical imaging (OPT/SPIM) provided exact cross-validation of prelabeled islet transplants in the pancreas. A small molecule was identified, which promisingly showed labeling of islets in vitro and in vivo. Further improvements on the target affinity of the β-cell specific nanocontainers will be done in the future.