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Development of 99mTc Radiopharmaceuticals for Sentinel Node Detection and Cancer Diagnosis
Closed for proposals
Project Type
Project Code
F22045CRP
1433Approved Date
Status
Start Date
Expected End Date
Completed Date
7 December 2010Description
Radioguided sentinel lymph node biopsy (SLNB) is used for the management of breast cancer and melanoma, predominantly in the early stages of disease for detection of affected lymph nodes in unpredictable locations. Radiopharmaceuticals based on 99mTc-colloids are currently used for sentinel node detection. Shortcomings of the existing agents include high retention at the site of injection, possibly masking uptake in nearby lymph nodes, limited uptake by sentinel nodes, use of biological products etc. The CRP intends to develop receptor specific radiopharmaceuticals with well defined particle size to overcome the above disadvantages. Use of 99mTc based radiopharmaceuticals for imaging of cancers as well as metastasis offers the possibility of cost effective application across a wider cross section of population. Combining the knowledge gained in the use of 99mTc novel cores with emerging synthetic techniques (e.g. click chemistry) could be used for making new labelled bio molecules for investigation as radiotracers for uptake by cancer cells. This might result in the development of new radiotracers/ radiopharmaceuticals and increase the expertise in the participating groups.
Objectives
The main objective of the project was to develop new technetium-99m molecular imaging agents for the detection of cancerous lesions and of the spread of the metastatic process with particular focus on superficial cancers such as breast cancer and skin melanoma.
Specific objectives
The main specific objective of the Coordinated Research Project (CRP) was to develop a new technetium-99m molecular imaging agent to display the lymph node nearest to the cancerous lesion. This diagnostic approach, called Sentinel Lymph Node Detection (SLND), is used for planning the therapeutic treatment for superficial cancers such as breast cancer and skin melanoma. The basic concept behind this method is that, for this type of cancers, the spread of the metastases from the primary tumour site always occurs through lymphatic drainage and, thus, the most proximal (sentinel) lymph node will be the first to receive the metastatic invasion. It follows that, after surgical resection of the primary tumour, the precise localization of this sentinel lymph node allows its removal and biopsy to assess whether the metastatic process has already affected it. This information proved to be crucial for planning the further therapeutic treatment of the patient. In fact, when the node is negative, there is no need to resort to surgical dissection of lymph nodes with clear benefits for the patient.
Collateral projects have been also pursued during the CRP and these were related to (a) the development of multimeric RGD peptides for the diagnosis of integrin-receptor expressing tumours and (b) the investigation of alternative chemical approach for the cost-effective preparation of novel technetium-99m molecular diagnostic agents.
The CRP program was divided into sub-programs each corresponding to a specific objective.
Subproject 1
- Design and synthesis of dextran multifunctional ligands with pendant mannose residues for interaction with macrophage’s receptors and suitable chelating groups for binding to 99mTc.
- In vitro evaluation of stability and binding affinity for mannose receptors and in vivo biological evaluation in animal models for sentinel node detection.
- Development of a ‘cold kit’ formulation for easy and reliable preparation of the new 99mTc radiopharmaceuticals to be distributed in Member States.
Subproject 2
- Preparation of functionalized gold nanoparticles as an alternative macromolecular substrate for the development of a mannose-receptor-mediated SLND imaging agent.
- Biological evaluation in animal models.
Subproject 3
- Development of an alternative synthetic approach for producing multimeric RGD peptides by attaching multiple peptides chains to functionalized polymeric dextran.
- Evaluation of the potential use of the resulting radiolabelled RGD-dextran conjugates for imaging integrin-receptor expressing cancers.
Subproject 4
- Application of novel chemical approaches, including ‘click chemistry’ and the chemistry of the cyclopentadienyl group (Cp), for developing multiple imaging probes for simultaneous imaging with different modalities (SPECT, MRI, Optical).
Impact
The most significant impact of the CRP comes from the development of the two new diagnostic Tc-99m radiopharmaceuticals for sentinel lymph node detection. This result will have obvious consequences on the scientific and medical community since new clinical investigations could be envisaged with the new tracers that might affect current approaches to the treatment of breast and melanoma cancers. It may also have an impact on the pharmaceutical industry since the new compounds could potentially replace the existing commercial agents based on Tc-99m-nanocolloids. In Member States, the results of this research work can surely contribute to expand the usage of a fundamental diagnostic approach and sharply improve current protocols, in particular, for the management of breast cancer patients.
Relevance
The results of the CRP are highly relevant for pursuing the overall objective of developing cost-effective radiopharmaceutical having improved diagnostic properties. The research work developed during the course of the project clearly demonstrates that this objective is achievable through a rational design and organization of the scientific contribution of the various participant groups.