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A new bio-sensor concept for medical diagnosis: targeted micro-bubbles and remote ultrasound transduction

Final Report Summary - TAMIRUT (A new bio-sensor concept for medical diagnosis: targeted micro-bubbles and remote ultrasound transduction)

Tamirut was a research project that demonstrated an innovative bio-sensor concept devoted to advanced medical diagnosis, in which the biological material is carried by targeted microbubbles injected inside the body and the transducer is remote. The remote transducer operates on the basis of the ultrasound response of such micro-bubbles, gathered and processed by an improved version of an ultrasound medical scanner (UMS). Targeted microbubbles (similar to the generic micro-bubbles composing the contrast agents actually used in medical echography) are designed to bind only to a desired target region: a bioconjugate ligand is attached to micro-bubble shells producing the adhesion of them to specific molecular signatures.

Such innovative bio-sensor could help medical professionals visualise tiny quantities of pathological tissue in patients and it could localise tumours in their very earliest stages of development and help doctors begin treatments much earlier, giving patients a much better chance of survival. The approach uses medical ultrasound, a safe technology most commonly used for pre-natal visualisation of the foetus and the imaging of other soft tissues.

To improve the sensitivity of this imaging technique, an ultrasound imaging system may sometimes inject a so-called contrast agent into patients, which greatly increases the scattering of the acoustic waves back to the probe. The developed micro bubble medium for this biosensor are specifically targeted to bind to specific molecular signature, expressed by a predefined type of cancer, present in the blood vessel. Specific signal processing capabilities integrated in an enhanced ultrasound equipment detect where these micro bubbles adhere to target cells, and reveal the presence of early-stage tumours.

Among many potential medical applications, the case study that was addressed in the Tamirut project concerns the early detection of the prostate cancer. Cancer is a growing concern all over the world. Prostate cancer is the most frequent cancer among men accounting for 12 % of all cancer cases overcoming also lung cancer accounting 'only' for 10 % of cases. Prostate cancer is still a rare event in men under 40's but with a rate destined to increase with the age. It has been calculated that a man out of six is destined to experience prostate cancer clinically evident in its life. Of cases of prostate cancer, 70 % arise in the peripheral zone, 15-20 % arise in the central zone, and 10-15 % arise in the transitional zone. Most prostate cancers are multifocal, with synchronous involvement of multiple zones of the prostate, which may be due to clonal and nonclonal tumors.

Unfortunately prostate cancer, for most part, is a silent disease for whom it is essential that specialist screening should be offered annually, beginning at age 50 years, to men who have at least a 10-year life expectancy and to younger men who are at high risk. PSA screening for prostate cancer is very sensitive tumoral marker, but it presents poor specificity. Risky, painful and costly biopsies need to integrate suspected occurrences of cancer to exclude the relevant number of false positives generated by PSA. Unfortunately, by biopsy a not insignificant number of false negative is present, delaying the cancer detection (prostate biopsy is a statistical sampling, and not a whole organ examination therefore then there are chances to miss the target).

The proposed bio-sensor goes in the direction to eliminate or strongly reduce this problem, offering a second degree of evaluation after PSA screening, sensitive and specific, able to examine the organ as a whole. Only an injection of targeted UCA and a subsequent examination by the advanced UMS are needed in order to achieve a better knowledge of the procedure. Furthermore, the proposed bio-sensor offers the possibility to examine the prostate as a whole, no area excluded, instead of considering only the restricted parts from where biopsy specimens are extracted. A small cancer can be missed from an examination by samples like biopsy. Sure this will grant a higher specificity to proposed bio-sensor. In addition, the process offers a simple, efficient and cost effective system also to monitor the results of the therapy.

The proposed new concept of bio-sensor system represents a highly complicated problem, which can be addressed only by duly combining know-how and skills owned by a variety of scientific and technological areas, putting together the necessary critical mass, and bringing together European-wide expertise and resources. Among the involved areas one can cite: molecular bioanalytical chemistry and bio-sensor technology, ultrasound micro-bubbles contrast agent production, advanced signal processing techniques, ultrasound probe construction, ultrasound scanner construction, micro-bubble / ultrasound signal interaction modelling techniques, as well as biomedical and clinical practice.

To address the case study of a biosensor for early detection of the prostate cancer, a collection of the overall medical needs and the consequent technical / scientific specifications of all bio-sensor components to face the prostate cancer case-study was organised. This actions left to the final selection of PSMA and tissue factor as possible endothelial markers (i.e. molecular signatures) which are over-expressed in the selected case study of prostate cancer and that it could match the requisite for the researched biosensor characteristics.

A solution based on the regression implemented by a support vector machine (SVM) has been developed and tested using simulated data for the measurement of the bubble concentration.

In last but not least fundamental we implemented the refined ligand-bearing microbubbles and were selected and tested the possible antibodies for their possible use with the two targets previously chosen: PSMA and Tissue factor. Two methods for the formulation of ligand-bearing microbubbles have been developed. The first one, based on streptavidinbiotin interaction, allows testing of target antibodies on a small scale, the second method aims at producing the Tamirut ultrasound contrast agent on a larger scale. Two antibodies against tissue factor were selected and tested. The antibody against PSMA selected is Abcam ab22335. From this individuated processes and solutions, microbubbles have been refined and made ready for the in vitro and in vivo final test of project proof of concept.

The positive proof of concept obtained as results of this project confirms that the development of novel ultrasound targeted micro-bubbles activated through remote ultrasound transduction is a new way to contribute in solving cancer diagnosis problems. Achieving the advances expected from the Tamirut project and demonstrating the feasibility of the novel approach, Tamirut partners potentially promote a new era of biosensors with wide capability of clinical applications. From the prostate cancer case-study is disclosing a very high potential of solutions for the diagnosis and the assessment of other cancer types and also other pathologies.

The need for clinical trials and of the novel biosensor for prostate cancer with all related necessary technological optimisaton and subsequent approval in humans means that the targeted microbubble agent is unlikely to be available for at least three / five years.

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