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Production of magnetosomes for magnetic hyperthermia treatment of glioblastoma

Start: 31 December 2013

End: 27 April 2017

Supervisors :
Edouard Alphandéry (Sorbonne Université - Société Nanobactérie), Jean-Pierre Valet

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Status: Defended

Doctoral dissertation - Raphael Le Fevre

The Nanobactérie company develops a thermal treatment against cancer using iron oxide nanoparticles biomineralized by bacterium said “magnetotactic”. These nanoparticles, also called magnetosomes, are injected in the tumor and then activated by an alternating magnetic field. Activated nanoparticles produce a localized rise in temperature or hyperthermia, triggering the destruction of the tumor while inducing no adverse effects on adjacent healthy tissues. Antitumor efficiency is ascribed to the number of hyperthermia sessions and to the temperature reach inside the tumor. This innovative thermal treatment is referred to as magnetic hyperthermia. Physicochemical properties of magnetosomes are ideal for magnetic hyperthermia treatment. By contrast to their chemical counterparts, magnetosomes display improved heating properties, high levels of chemical purity and crystallinity, narrow particle size distributions and homogeneous shapes. 
In the first part of this work, we developed an effective and reproducible method, in fermenter, of magnetosome production by Magnetospirillum gryphiswaldense MSR-1, a model magnetotactic bacterium. Key parameters for magnetosomes biosynthesis such as a constant iron intake and low oxygen concentration (pO2 < 0,1%) are ideally monitored in a fermenter and critical to obtain high yields of magnetosomes compatible with a pharmaceutical production. Following the fermentation process, magnetosomes are extracted from MSR-1 bacterium, purified and coated with a biocompatible polymer, poly-L-lysine, which is nontoxic, apyrogenic and injectable. Magnetosomes poly-L-lysine (M-PLL) properties meet the requirements of ISO 10993 standards assessing the biocompatibility of medical devices. M-PLL antitumor efficiency for magnetic hyperthermia treatment is finally assessed in subcutaneous glioblastoma tumours in mice. Glioblastoma or astrocytoma grade IV, is the most frequent, aggressive and deadly tumor of the central nervous system. A magnetic hyperthermia treatment protocol is proposed, in which M-PLL are administered at the centre of the tumor followed by repeated application of an alternating magnetic field operating at a regulated strength ranging from 11 to 31 mT in order to maintain intratumoral temperatures between 43-46 °C. Antitumor efficiency was significant in all mice treated with M-PLL with full tumor disappearances achieved in 50% of mice and tumor growth delayed in all remaining mice. The present thesis work shows the relevance of magnetosomes for magnetic hyperthermia treatment of aggressive tumors of the central nervous system and encourages future consideration of the use of this therapy in larger animals, and then humans.
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Doctoral dissertation - Raphael Le Fevre The Nanobactérie company develops a thermal...