Cancer therapy using nanoformulated substances: scientific, regulatory and financial aspects

International audienceSeveral nanoformulated anti-cancer substances are currently commercialized or under development. Pre-clinical and clinical results have revealed better properties, that is, larger efficacy and lower toxicity for these substances than for conventional anti-cancer treatments. Here, we review the development of several of these substances such as Marqibo, Myocet, Doxil, DaunoXome, MM398, MM302, Mepact, Versamune, Thermodox, Depocyt, Livatag, Abraxane, Eligard, Opaxio, Zinostatin Stimalamer (SMANCS), Pegasys and PegIntron, BIND-014, CRLX-101, Oncaspar, Neulasta, Aurimmune, Auroshell, AuNPs, Nanotherm, NanoXray, Magnetosome chains, Kadcyla (T-DM1), Ontak (DAB/IL2), Gendicine and Curcumin. We describe their specific properties, such as their stability, solubility, mean of administration or targeting, distribution, metabolism and toxicity. We discuss their categorization as medical devices or drugs, their fabrication process within a regulatory environment as well as intellectual property and financial aspects that are all essential to enable their industrial development

Biocompatible Coated Magnetosome Minerals for Application in the Magnetic Hyperthermia Treatment of Tumors

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Biocompatible coated magnetosome minerals with various organization and cellular interaction properties induce cytotoxicity towards RG-2 and GL-261 glioma cells in the presence of an alternating magnetic field

Abstract Background Biologics magnetics nanoparticles, magnetosomes, attract attention because of their magnetic characteristics and potential applications. The aim of the present study was to develop and characterize novel magnetosomes, which were extracted from magnetotactic bacteria, purified to produce apyrogen magnetosome minerals, and then coated with Chitosan, Neridronate, or Polyethyleneimine. It yielded stable magnetosomes designated as M-Chi, M-Neri, and M-PEI, respectively. Nanoparticle biocompatibility was evaluated on mouse fibroblast cells (3T3), mouse glioblastoma cells (GL-261) and rat glioblastoma cells (RG-2). We also tested these nanoparticles for magnetic hyperthermia treatment of tumor in vitro on two tumor cell lines GL-261 and RG-2 under the application of an alternating magnetic field. Heating, efficacy and internalization properties were then evaluated. Results Nanoparticles coated with chitosan, polyethyleneimine and neridronate are apyrogen, biocompatible and stable in aqueous suspension. The presence of a thin coating in M-Chi and M-PEI favors an arrangement in chains of the magnetosomes, similar to that observed in magnetosomes directly extracted from magnetotactic bacteria, while the thick matrix embedding M-Neri leads to structures with an average thickness of 3.5 µm2 per magnetosome mineral. In the presence of GL-261 cells and upon the application of an alternating magnetic field, M-PEI and M-Chi lead to the highest specific absorption rates of 120–125 W/gFe. Furthermore, while M-Chi lead to rather low rates of cellular internalization, M-PEI strongly associate to cells, a property modulated by the application of an alternating magnetic field. Conclusions Coating of purified magnetosome minerals can therefore be chosen to control the interactions of nanoparticles with cells, organization of the minerals, as well as heating and cytotoxicity properties, which are important parameters to be considered in the design of a magnetic hyperthermia treatment of tumor

Biocompatible and stable magnetosome minerals coated with poly- l -lysine, citric acid, oleic acid, and carboxy-methyl-dextran for application in the magnetic hyperthermia treatment of tumors

International audienceMagnetic hyperthermia, in which magnetic nanoparticles are introduced into tumors and exposed to an alternating magnetic field (AMF), appears to be promising since it can lead to increased life expectancy in patients. Its efficacy can be further improved by using biocompatible iron oxide magnetosome minerals with better crystallinity and magnetic properties compared with chemically synthesized nanoparticles (IONP – Iron Oxide Nanoparticles). To fabricate such minerals, magnetosomes are first isolated from MSR-1 magnetotactic bacteria, purified to remove potentially toxic organic bacterial residues and stabilized with poly-L-lysine (N-PLL), citric acid (N-CA), oleic acid (N-OA), or carboxy-methyl-dextran (N-CMD). The different coated nanoparticles appear to be composed of a cubo-octahedral mineral core surrounded by a coating of different thickness, composition, and charge, and to be organized in chains of various lengths. The in vitro anti-tumor and heating efficacies of these nanoparticles were examined by bringing them into contact with GL-261 glioblastoma cells and by applying an AMF. This led to a specific absorption rate of 89–196 W gFe−1, measured using an AMF of 198 kHz and 34–47 mT, and to percentages of tumor cell destruction due to the exposure of the nanoparticles to the AMF of 10 ± 3% to 43 ± 3% depending on the coating agent. These results show the potential of this protocol for the tumor treatment by magnetic hyperthermia

Enhanced antitumor efficacy of biocompatible magnetosomes for the magnetic hyperthermia treatment of glioblastoma

In this study, biologically synthesized iron oxide nanoparticles, called magnetosomes, are made fully biocompatible by removing potentially toxic organic bacterial residues such as endotoxins at magnetosome mineral core surfaces and by coating such surface with poly-L-lysine, leading to magnetosomes-poly-L-lysine (M-PLL). M-PLL antitumor efficacy is compared with that of chemically synthesized iron oxide nanoparticles (IONPs) currently used for magnetic hyperthermia. M-PLL and IONPs are tested for the treatment of glioblastoma, a dreadful cancer, in which intratumor nanoparticle administration is clinically relevant, using a mouse allograft model of murine glioma (GL-261 cell line). A magnetic hyperthermia treatment protocol is proposed, in which 25 µg in iron of nanoparticles per mm3 of tumor are administered and exposed to 11 to 15 magnetic sessions during which an alternating magnetic field of 198 kHz and 11 to 31 mT is applied for 30 minutes to attempt reaching temperatures of 43-46 °C. M-PLL are characterized by a larger specific absorption rate (SAR of 40 W/gFe compared to 26 W/gFe for IONPs as measured during the first magnetic session), a lower strength of the applied magnetic field required for reaching a target temperature of 43-46 °C (11 to 27 mT compared with 22 to 31 mT for IONPs), a lower number of mice re-administered (4 compared to 6 for IONPs), a longer residence time within tumours (5 days compared to 1 day for IONPs), and a less scattered distribution in the tumour. M-PLL lead to higher antitumor efficacy with full tumor disappearances achieved in 50% of mice compared to 20% for IONPs. This is ascribed to better ability of M-PLL, at equal iron concentrations, to maintain tumor temperatures at 43-46°C over a longer period of times