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BIBI-CHEMAP
FunderFrench National Research Agency (ANR)
Funder Contribution €429,997.00
DurationFrom 01 Oct 2012
Project codeANR-12-BS07-0006
Open Access mandatePublications: NoResearch data: No
Identifiers
Description
Alpha-radioimmunotherapy (alpha-RIT) represents an emerging therapeutic modality for tumour treatment. In contrast with beta emitting radionuclides, the energy emissions of alpha-particle decays are directly deposited over a very short distance (40–100 micro-m), resulting in high linear energy transfer. The shorter path limits toxicity to normal tissue adjacent to tumour. As such, alpha-emitting radionuclides appear ideal for specific treatment of smaller tumour burden, disseminated disease, and micrometastatic disease. Alpha-emitters currently under investigation for RIT applications include: 212Bi (t1/2 = 60.6 minutes), 213Bi (t1/2 = 45.6 minutes), and 211At (t1/2 = 7.2 hours). Although ligands as CyDTPA or DOTA have been known over 25 years, they are still not validated in clinical applications. Additionally, for clinical alpha-radioimmunotherapy, the possibility of generating 212Bi from 212Pb via a beta decay (in-situ generator) can be crucial, since it would become possible to generate the alpha emitter in situ, to overcome its rather short period. We propose to investigate various series of new chelating molecules and to study their possible vectorization for the medical application of bismuth alpha-emitter isotopes (212 and 213) in radioimmunotherapy. To do so, two different families of ligands, porphyrins (PM) and tetraaza macrocycles (4NM) will be investigated. Where they appear different in their structure, both series are efficient chelators of cations. However, they both need to be chemically tuned to optimize their chelation of bismuth. Speaking of radiochemistry, where both bismuth isotopes are among the best candidates for this application, their might suffer from a short period. However, this disadvantage can be bypassed if one can pre-complex their direct radioactive parent. This appears possible in the case of bismuth 212 as its direct radioactive parent is lead 212. An exciting prospect is also represented by the investigation of new ditopic mixed chelates which will exhibit a specific site for each element. Actually, all the scientific backgrounds and technical structures necessary for this very specific investigation are present in the west part of France. Indeed, the close geographic proximity of organic chemists and biologists will allow a permanent feedback between the initial first-generation chelates and the final bifunctional chelates developed towards a potential application in nuclear medicine. Furthermore, a direct collaboration with radiochemists from Trans-Uranyl Elements (ITU) in Karlsruhe (Germany) is included and guaranties a permanent access to the various radioactive elements required in this proposal.
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Alpha-radioimmunotherapy (alpha-RIT) represents an emerging therapeutic modality for tumour treatment. In contrast with beta emitting radionuclides, the energy emissions of alpha-particle decays are directly deposited over a very short distance (40–100 micro-m), resulting in high linear energy transfer. The shorter path limits toxicity to normal tissue adjacent to tumour. As such, alpha-emitting radionuclides appear ideal for specific treatment of smaller tumour burden, disseminated disease, and micrometastatic disease. Alpha-emitters currently under investigation for RIT applications include: 212Bi (t1/2 = 60.6 minutes), 213Bi (t1/2 = 45.6 minutes), and 211At (t1/2 = 7.2 hours). Although ligands as CyDTPA or DOTA have been known over 25 years, they are still not validated in clinical applications. Additionally, for clinical alpha-radioimmunotherapy, the possibility of generating 212Bi from 212Pb via a beta decay (in-situ generator) can be crucial, since it would become possible to generate the alpha emitter in situ, to overcome its rather short period. We propose to investigate various series of new chelating molecules and to study their possible vectorization for the medical application of bismuth alpha-emitter isotopes (212 and 213) in radioimmunotherapy. To do so, two different families of ligands, porphyrins (PM) and tetraaza macrocycles (4NM) will be investigated. Where they appear different in their structure, both series are efficient chelators of cations. However, they both need to be chemically tuned to optimize their chelation of bismuth. Speaking of radiochemistry, where both bismuth isotopes are among the best candidates for this application, their might suffer from a short period. However, this disadvantage can be bypassed if one can pre-complex their direct radioactive parent. This appears possible in the case of bismuth 212 as its direct radioactive parent is lead 212. An exciting prospect is also represented by the investigation of new ditopic mixed chelates which will exhibit a specific site for each element. Actually, all the scientific backgrounds and technical structures necessary for this very specific investigation are present in the west part of France. Indeed, the close geographic proximity of organic chemists and biologists will allow a permanent feedback between the initial first-generation chelates and the final bifunctional chelates developed towards a potential application in nuclear medicine. Furthermore, a direct collaboration with radiochemists from Trans-Uranyl Elements (ITU) in Karlsruhe (Germany) is included and guaranties a permanent access to the various radioactive elements required in this proposal.
