Nanoparticle-Enhanced molecular Fluorescence-Endoscopy for detection of colon cancer (NanoEFEct)

The Project will adapt nanoparticles which are presently available, for use in a different planned clinical application. The nanoparticles base on human serum albumin and in the present version are lectin-targeted to molecular targets (oligolactosamines) present in the apical glycocalyx of vascular endothelial cells. The nanoparticles bear gadolinium-DTPA chelates in order to give strong signals in molecular imaging by magnetic resonance imaging, and have been used to demonstrate molecular imaging of the vascular wall in living rats. The Project will synthesize and adapt these nanoparticles for use in EpCAM-targeted molecular imaging in fluorescence endoscopy, aiming to develop agents of diagnostic value in clinical colonoscopy. The modified nanoparticles will be designed to reveal the presence of early-stage carcinomas in the colon and rectal walls of human subjects undergoing screening colonoscopy. They will be bear anti-EpCAM antibodies of the type already licensed for therapeutic applications in patients. They will bear fluorochromes emitting in the Near InfraRed part of the optical spectrum. These Aims will need to be realized by step-by-step modification of the existing nanoparticle versions. The lectin presently used will be replaced by anti-EpCAM antibodies, and the signaling group Gd-DTPA will be replaced by a licensed fluorochrome such as IndoCyanin Green (ICG). These replacement actions are straightforward and involve no theoretical difficulties, and are expected to proceed without problem. However, to optimize the new version of the nanoparticles for use in screening fluoro-endoscopy of the colon, a considerable amount of basic research activity must take place. The ratios of the targeting groups (anti-EpCAM) and the signaling groups (ICG) per nanoparticle will be investigated and optimized, and the resulting nanoparticles will be tested by incubation with vital biopsies of human colon wall ex situ (ethic commission approval already obtained). The optical equipment for this testing will be assembled into a semi-permanent form for use in this testing. The nanoparticles selected after this ex situ testing will be applied in both topically and intravenously in a mouse model (international partner) and the biodistribution, clearance, and detailed pharmacokinetics of the nanoparticles will be investigated, in order to eliminate any toxic effects and to elucidate the nanoparticle-tissue interactions. At all steps of the work the Project will store data in collated form and generate Standard Operating Protocols for use in later translational work.

Our Project developed a new method for the early detection of colon cancer, based on the use of nanoparticles during cancer screening. Colon cancer is one of the commonest cancers, worldwide there are about 1.4 million new cases per year. It has a high death rate, largely due to the difficulty of diagnosing the early stages: even in the carefully cleaned gut wall it is not always possible to recognize the cancer cells with certainty. At this point our project makes its contribution: in our concept, with the help of nanoparticles the cancer cells are made to light up brightly, making them much easier to detect, which aids the diagnosis. During the endoscopic examination of the colon, spraying the nanoparticles onto suspicious sites in the gut wall causes a bright image to appear at malignant sites when these are illuminated by a special light, thus signaling the presence of cancer. Our projects Principle Investigator was the Coordinator in the European Unions international translational cancer research consortial project NanoEFEct. Three members of the NanoEFEct consortium, including our Innsbruck team and partners in Trondheim (Norway) and Porto (Portugal), created different types of nanoparticles and tested one anothers products. Our fourth member in Erlangen (Germany) was a clinical partner, at the university clinic of gastroenterology, and tested the nanoparticles produced by the three nanoparticle laboratories in studies of cancer cells and of mice bearing colon cancers. Our fifth partner was CESAR (Vienna), an Austrian management team with experience in coordinating clinical research. All three scientific partners created nanoparticles that fulfill the aim of lighting up colon cancers, both in human materials and in mouse research models. This consortial research result proved conclusively that our aim is feasible, that our concept of aiding diagnosis by generating a bright image of each tumour in the colon wall is proven to work. Our successful concept functions in the laboratory and now needs to be developed for use in clinics. In further work we will study the advantages and disadvantages of each of the three different nanoparticle versions, in order to identify the most effective version and the safest version. In this project we aimed to create knowledge useful in developing products for clinical use in colon cancer. Our diagnostic procedure can however be adapted easily for use in the diagnosis of other types of cancer, such as for example lung cancers, ear-nose-throat cancers, and genito-urinary cancers. The social and economic impact of our work is therefore potentially extremely large. In future work we will focus on developing safe and effective nanoparticles for use in diagnosis of several other major diseases.