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We have measured the resistivity of magnetically doped Ag:Mn mesoscopic wires as a function of temperature and magnetic field. The doping has been made using ion implantation, allowing a distribution of the dopants in the middle of the sample. Comparison with an undoped sample, used as a reference sample, shows that the resistivity of the doped sample exhibits nonmonotonic behavior as a function of both magnetic field and temperature, revealing the competition between the Kondo effect and the RKKY interactions between spins. This proves that transport measurements are still a reliable probe of the spin-glass transition in nanoscopic metallic wire doped using implantation.

Marion Paolini,1,2 Laurence Poul,1 Céline Berjaud,1 Matthieu Germain,1 Audrey Darmon,1 Maxime Bergère,1 Agnès Pottier,1 Laurent Levy,1 Eric Vibert2 1Nanobiotix, Paris, 2UMR-S 1193 INSERM/Paris-Sud University, Centre Hépato-Biliaire, Hôpital Paul Brousse, Villejuif, France Abstract: Most drugs are metabolized by hepatic cytochrome P450 3A4 (CYP3A4), resulting in their reduced bioavailability. In this study, we present the design and evaluation of biocompatible nanocarriers trapping a natural CYP3A4-inhibiting compound. Our aim in using nanocarriers was to target the natural CYP3A4-inhibiting agent to hepatic CYP3A4 and leave drug-metabolizing enzymes in other organs undisturbed. In the design of such nanocarriers, we took advantage of the nonspecific accumulation of small nanoparticles in the liver. Specific targeting functionalization was added to direct nanocarriers toward hepatocytes. Nanocarriers were evaluated in vitro for their CYP3A4 inhibition capacity and in vivo for their biodistribution, and finally injected 24hours prior to the drug docetaxel, for their ability to improve the efficiency of the drug docetaxel. Nanoparticles of poly(lactic-co-glycolic) acid (PLGA) with a hydrodynamic diameter of 63nm, functionalized with galactosamine, showed efficient invitro CYP3A4 inhibition and the highest accumulation in hepatocytes. When compared to docetaxel alone, in nude mice bearing the human breast cancer, MDA-MB-231 model, they significantly improved the delay in tumor growth (treated group versus docetaxel alone, percent treated versus control ratio [%T/C] of 32%) and demonstrated a major improvement in overall survival (survival rate of 67% versus 0% at day 55). Keywords: hepatic metabolism, CYP3A4, PLGA nanoparticles, hepatocyte targeting, galactosamine

Many therapeutic agents offer a low useful dose (dose responsible for efficacy)/useless dose (dose eliminated or responsible for toxicity) ratio, mainly due to the fact that therapeutic agents must ensure in one single object all the functions required to deliver the treatment, which leads to compromises in their physico-chemical design. Here we introduce the concept of priming the body to receive the treatment by uncorrelating these functions into two distinct objects sequentially administered: a nanoprimer occupying transiently the main pathway responsible for therapeutic agent limited benefit/risk ratio followed by the therapeutic agent. The concept was evaluated for different nature of therapeutic agents: For nanomedicines we designed a liposomal nanoprimer presenting preferential hepatic accumulation without sign of acute toxicity. This nanoprimer was able to increase the blood bioavailability of nanomedicine correlated with a lower hepatic accumulation. Finally this nanoprimer markedly enhanced anti-tumor efficacy of irinotecan loaded liposomes in the HT-29 tumor model when compared to the nanomedicine alone. Then, for small molecules we demonstrated the ability of a cytochrome inhibitor loaded nanoprimer to increase efficacy of docetaxel treatment. These results shown that specific nanoprimers could be designed for each family of therapeutic agents to answer to their specific needs.

Purpose: This phase I study aimed to determine the recommended dose (RD), safety profile, and feasibility of a procedure combining intratumoral injection of hafnium oxide nanoparticles (NBTXR3; a radioenhancer) and external beam radiotherapy (EBRT) for preoperative treatment of adults with locally advanced soft tissue sarcoma (STS). Experimental Design: Patients had a preoperative indication of EBRT for STS of the extremity or trunk. Baseline tumor volume (TV) was calculated by MRI. NBTXR3 was injected percutaneously into tumors at 53.3 g/L. Dose escalation was based on four levels equivalent to 2.5%, 5%, 10%, and 20% of baseline TV. NBTXR3 was visualized in the tumor 24 hours postinjection, and EBRT was initiated (50 Gy over 5 weeks). Surgery was performed 6 to 8 weeks after EBRT completion. Results: Twenty-two patients completed NBTXR3 injection, EBRT, and surgery and were followed for a median 22 months (range, 6–40). At NBTXR3 20% of TV, two dose-limiting toxicities occurred: injection-site pain and postoperative scar necrosis. The RD was defined as 10%. No leakage of NBTXR3 into surrounding tissues occurred; intratumor NBTXR3 levels were maintained during radiotherapy. At the RD, median tumor shrinkage was 40% (range 71% shrinkage, 22% increase); median percentage of residual viable tumor cells was 26% (range, 10%–90%). Patients receiving 20% of TV demonstrated pathologic complete responses. Seven grade 3 adverse events occurred, which were reversible. Conclusions: A single intratumoral injection of NBTXR3 at 10% of TV with preoperative EBRT was technically feasible with manageable toxicity; clinical activity was observed. Clin Cancer Res; 23(4); 908–17. ©2016 AACR.

Improved drug delivery control during chemotherapy is a major concern to increase their therapeutic index. Drug accumulation in solid tumor can be visualized using MRI contrast agent such as iron oxide nanoparticles encapsulated in liposomes. Once accumulated in tumor, the combination of a thermosensitive composition with an external source of activation allows local release of drug. MRI guided-High intensity focused ultrasound (HIFU) represents a non invasive technique to generate local hyperthermia for drug release of thermosensitive magnetoliposomes (TSM). In this study we performed encapsulation of ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) in thermosensitive liposomes to obtain TSM. Magnetic behavior of this MRI contrast agent was observed during TSM membrane permeabilization. For this, measurement of transverse and longitudinal relaxivities on MRI, and real time experiments were performed on TSM samples loaded with USPIO during heating using a water bath or HIFU. Results showed significant differences for MRI signal enhancement and relaxivities ratios before and after heating, which were absent for non-thermosensitive liposomes and free nanoparticles used as controls. Thus, incorporation of USPIO as MRI-contrast agents into thermosensitive liposomes should, besides TSM tumor accumulation, allows the visualization of TSM membrane permeabilization upon temperature elevation. In conclusion, HIFU under MR image guidance in combination with USPIO loaded thermosensitive liposomes as drug delivery system has the potential for a better control of drug delivery and to increase the therapeutic index of chemotherapy.

International audience; The crystallization route - calcination or hydrothermal ripening - of an amorphous hafnium and germanium oxide coprecipitate determines the X/UV conversion properties of the resulting hafnium germanate (HfGeO4). The calcination of the amorphous precipitate leads to micrometric aggregated particles exhibiting strong X/UV conversion whereas its hydrothermal crystallization resulted in well individualized nanoparticles with no X/UV conversion property. To explain these phenomena, the crystalline structure and chemical composition of the final products were investigated with X-ray diffraction (XRD) and inductively coupled plasma-mass spectrometry (ICP-MS). The key result is that germanium is partially solubilized from the amorphous precursor in hydrothermal conditions, resulting in the crystallization of a Ge deficient hafnium germanate possessing no X/UV conversion properties.

URL: http://www-spht.cea.fr/articles/s00/001 Effets de taille dans les propriétés magnétiques statiques et dynamiques de nanoparticules de Cd$_{1-y}$Mn$_y$S; Magnetic properties of Cd$_{1-y}$Mn$_y$S nanocrystals have been studied. They vary with the particle size and markedly differ from those observed in the bulk phase, in particular their interactions drastically increase compared to those observed in the latter case. A Mn$^{2+}$-Mn$^{2+}$ interaction enhancement with decreasing size involves changes in the magnetic phase diagram. For 4nm nanocrystals, a spin glass phase can be assumed.