Blanc SIMI 7 - Blanc - SIMI 7 - Chimie moléculaire, organique, de coordination, catalyse et chimie biologique

BIsmuth BIfunctional CHElates for Medical APplications of alpha-emitters: design, synthesis, and radiolabelling – BIBI-CHEMAP

Targeting isolated cells diseases with alpha-emitting bismuth complexes

Alpha emitters have the property of releasing a high (destructive) energy at a very small distance of the order of five cells. We seek to develop chelates able of carrying one of these metals (bismuth) close to the celll to destroy cells responsible for various pathologies. Thus, rapid complexation of bismuth as well as targeting are two critical factors.

Preparation of alpha-emitters vectors for the eradication of diseases related to isolated and / or circulating cells

Large tumor masses may be currently treated with beta emitters vectors such as yttrium. However, such vectors are not suitable at all for the treatment of diseases related to isolated and / or circulating cells. For these conditions, it is indeed necessary to use alpha emitters, exhibiting a higher linear energy transfer (LET), together with a lower range.<br />Our goal is to prepare suitable vectors for these diseases,specific of the element to carry. An alternative strategy consists of coordinating the father radioactive element.

The idea to deliver a toxic molecule close to its target (targeting) is certainly not new. However, it should be noted that in the context of radioactive elements, whatever the element considered, the same ligands are commonly used. We believe that this is a major drawback. Indeed, depending on the characteristics of the radioactive element considered, a specific ligand must be designed. The nature of this ligand will obviously depend on the coordination chemistry of the element to complex. This is the strategy that we have decided to apply. In addition, for the concept of pre-complexed radioactive parent in order to have more time to convey his radioactive son, that remains the actual toxic agent, one must design and prepare a ligand that takes into account the characteristics (necessarily different) of both the father and son elements. This molecule is therefore a compromise, but a calculated compromise.
In addition, during a radioactive treatment, and whatever the element considered, the latter is included in a decay chain. This means that different elements will be generated by reactions with periods very often quite different between a few seconds and a few days!. Therapy that uses radioactive elements must therefore take into account these elements. This is the second key point of our strategy. We study and consider the coordination chemistry of virtually all components of the decay chain of bismuth and synthesized a series of chelates which coordinates most of these elements. This should minimize radioactive contamination of undesired targets.

The specification of the possible application of such therapy is severe for the coordination chemist. In fact, we had to prepare stable complexes that form but also very fast in solutions as close as possible physiological liquids at room temperature. In order to do this, we had to look at the fundamental coordination chemistry of these elements (those in the decay chain of bismuth) applied to a very specific type of ligand: the porphyrin. Moreover, it is not a simple porphyrin but a variant that has «decoration« very special for which we have filed a patent.
If the final application of these molecules is the development of an alpha-radioimmunotherapy diseases circulating cells, coordination chemistry developed upstream can already consider possible applications in areas of applications areas as diverse as bistable molecules or molecular switches. This study also shed some light and knowledge quite new on the fundamental mechanisms that lead to the formation of a complex in a general sense.
This should lead in the medium term to all new international collaborations with internationally renowned groups working on the coordination chemistry of porphyrins.

This project highlights the importance of designing molecules to dedicated tasks specifically developed for a specific purpose. In the field of new therapies based on coordination chemistry, it is clear that this strategy is rarely applied.
It could be used in a more routinely way providing suitable financial resources, in both critical areas such as medicine and the environment. Indeed, in this last example, we know the environmental problems are caused by pollutants that we are not able to chelate and eliminate selectively. Similarly, in medicine, theragnostic various molecules are developed based on the coordination of various chemical elements in a non optimized way. Again, purposedly designed molecules would be very dedicated in favor of more effective tasks, and thus with a lower final cost.

Since the begining of this project, significant results are relevant to synthetic and coordination levels and have so far produced:
- 2 high impact factor (> 5) publications in Chem. Eur; J. published by the Rennes coordinator team
- 1 national patent (with extension to the international level currently filled) obtained by P2 (Brest)

Besides these three major scientific productions, the consortium has given close to a dozen of lectures and oral/poster communications. Although less important in terms of intellectual properties, these communications are yet important for the latge public informatioon.

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.

Project coordination

Bernard Boitrel (Sciences Chimiques de Rennes) –

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


DC-INSERM U 892 Département de Cancérologie - Institut de Recherche thérapeutique
SCR - U-RENNES1 Sciences Chimiques de Rennes
LCEMCA - CNRS Bretagne UMR 6521 Laboratoire de Chimie, Electrochimie Moléculaires et Chimie Analytique

Help of the ANR 429,997 euros
Beginning and duration of the scientific project: September 2012 - 36 Months

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