Search

Whole blood hafnium concentrations for each patient following NBTXR3 injection. Quantification of NBTXR3 in the blood was performed to evaluate passage into the systemic circulation. The hafnium component of NBTXR3 was quantified through inductively coupled plasma mass spectrometry (ICP-MS). Whole blood samples were collected on Day 1: before injection, immediately after the injection start, at the end of the injection, 5, 10, 15, 60, 120 and 240 minutes after completion of the injection; and on Day 2. Three additional blood samples were collected during radiotherapy, between the 11th and 20th radiotherapy sessions. One blood sample was also collected prior to surgery.

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.

NBTXR3 Injection _ DCE US. Dynamic contrast-enhanced ultrasonography (DCE-US) was performed to examine treatment-related changes to the tumor

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

Radio-enhancers, metal-based nanosized agents, could play a key role in oncology. They may unlock the potential of radiotherapy by enhancing the radiation dose deposit within tumors when the ionizing radiation source is 'on', while exhibiting chemically inert behavior in cellular and subcellular systems when the radiation beam is 'off'. Important decision points support the development of these new type of therapeutic agents originated from nanotechnology. Here, we discuss from an industry perspective, the interest of developing radio-enhancer agents to improve tumor control, the relevance of nanotechnology to achieve adequate therapeutic attributes, and present some considerations for their development in oncology.

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.

The French Law of Arbitration by Jean Robert and Thomas E. Carbonneau Published by Mathew Bender, New York, 1983 (Nine Chapters plus Preface, Table of Contents, Appendices, Selected Bibliography and Index). Price $75 US. A Swiss-American Perspective of a Franco-American Treatise Gallic arbitration law holds a special fascination for the student of international commercial dispute resolution, whether scholar or practitioner, connoisseur or novice. France's popularity as an arbitration situs may explain some of this interest.1 However, the deeper intellectual significance of the subject probably lies in the historical richness of the French judicial and legislative elaboration of a special status for international commercial arbitration. The development of French arbitration law represents a paradigm of the modern trend toward ‘delocalised’ procedure,2 in which arbitral autonomy is restricted by only a bare minimum of local procedural imperatives. The French Law of Arbitration is a first-rate adaptation of Jean Robert's classic treatise on French arbitration law, first published in 1937, and now in its fifth edition.3 But it is much more. The authors' guide to the interaction of judge and arbitrator in France provides an interpretation of civil law concepts for the common law mind that constitutes valuable scholarship in its own right. The work is an intellectually rewarding, practically useful, and elegantly styled contribution to the growing literature in the field.4 This effort illustrates the potential for fruitful co-operation among comparativists from divergent backgrounds, and should stimulate further inquiry into broader questions relating to the way curial norms of the place of arbitration apply to international arbitral proceedings. The experience, talent and credentials of the authors, as well as the reputation of Columbia's Parker School, under whose auspices the book was published, would lead one to expect a quality book. This expectation is not disappointed. Jean Robert has been a distinguished member of the Paris bar for well over half a century. Thomas Carbonneau is a tenured member of the faculty of Tulane Law School and Assistant Director of the Eason-Weisman Center …

Nanomedicines are mainly used as drug delivery systems; here we evaluate a new application - to inhibit a drug's metabolism thereby enhancing its effective dose. Micelles containing the natural furanocoumarin 6',7'-dihydroxybergamottin (DHB), a known CYP450 inhibitor, were developed to transiently block hepatic CYP450-mediated drug metabolism and increase the bioavailability of the oncology drug docetaxel. Administered in mice 24h prior to the drug, DHB-micelles enhanced antitumor efficacy in the tumor xenograft models HT-29 and MDA-MB-231, when compared to the drug alone. These DHB-micelles have similar composition to marketed docetaxel-micelles for human use. Despite not being optimized in terms of targeting hepatocytes, they do represent the first injectable example of nanosized metabolism-blocking agents and open the way for further work on such nanomedicines in man.

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.

O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1

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.

Since the early years of 2002, INRA and CIRAD in Guadeloupe have implemented complementary yam breeding programs to develop highly performant and locally well-adapted yam hybrids to fit both producers and consumer's requirements, yielding to nearly 20 pre-selected innovative cultivars. In 2012, a multi-local, multi-partenarial and participative field plot network was implemented to achieve evaluation of cultivar performance at field scale in contrasted geographical and productive environments throughout Guadeloupe. During two to three crop cycles, several agronomic and qualitative indicators selected by producers were followed, registers and combined in a collaborative database. Once formatted, data will be used to develop computer-based decision tools to help growers and technical advisors with selection of best-adapted cultivars to specific growing production or final use. Though this collaborative platform, various actors such as research scientists, breeders, technical advisors and producers have experimented and optimized effective yam breeding network to serve as a model for evaluation of any other tuber crops in Guadeloupe.

Yam (Dioscorea spp) is an annual tuber crop which is an important food crops in intertropical diets. Its area of cultivation varies from Japan, Western Africa, to the Caribbean with a wide diversity of cropping systems and cultivars. Among them, the yam cropping system with the “gutter-type tuber-support-container” in Japan allows for a sustainable increase of the graded tuber production. The main objective of this preliminary study is to test the adaptation of this yam cropping system under our Caribbean conditions and to select cultivars adapted to this system. The experiment was set in 2015 on the INRA experimental station in Duclos where 7 cultivars of D. alata were planted in gutters with a high density. The use of the “gutter-type tuber-support-container” coupled to the use of compost and paper mulch can intensify in a sustainable way yam-based cropping systems while avoiding the use of chemicals (mineral fertilizers, herbicides...). First results are promising, especially for 2 cultivars from Vanuatu, called Wanorak and Nepelev, which show very good yields (50t.ha-1) and grade (1 meter length for 1.4 kg in average per tuber). This type of cropping system could represent a sustainable alternative for local communities for instance. We still need to validate these results and to realize a technical-economical analysis of the performance of such system.

Nanomedicine (2014) 9(4), 389–391 ISSN 1743-5889 Dr Laurent Levy speaks to Hannah Stanwix, Commissioning Editor. Dr Levy has over 20 years’ experience in nanomedicine, supported by a solid understanding of physics, chemistry and biology. He obtained his doctorate in nanotechnology from the Pierre-andMarie-Curie University and the CEA (France), before pursuing a postdoctoral fellowship at the Institute for Lasers, Photonics and Biophotonics at the State University of New York, USA. Here, Dr Levy collaborated with the Director of the Institute, Paras Prasad, a key scientist working in the nanophotonic and nanobiotech field, to develop a unique vision for adopting nanotechnology to treat cancer. Dr Levy’s cutting-edge biotechnology and nanotechnology research culminated in the development of a nanomedicine platform called NanoXray to address the biggest drawbacks of radiation therapy, namely, the destruction of healthy tissue, among other adverse effects, caused by the high radiation doses necessary to destroy tumor targets. In 2003, Dr Levy cofounded Nanobiotix, a Paris-based nanomedicine company pioneering novel approaches for the local treatment of cancer. Currently, Dr Levy is involved in nanomedicine-focused international groups and think-tanks, aside from being an expert for EU funding programs. He is the ViceChairman of the European Technology Platform on Nanomedicine (ETPN) and the author of 35 international scientific publications and several patent applications. Europe as leaders in nanomedicine: let’s go for it!

Introduction: The benefit of a nanomedicine is due to its bioavailability, its intrinsic efficacy balanced with its toxicity profile. The nanomedicine should exhibit sufficient blood bioavailability for efficient accumulation at the target site. So far, a large part of the administered dose remains useless due to the high rate of clearance by the mononuclear phagocytic system (mainly by hepatic Kupffer cells). Enhanced bioavailability can be achieved by modifying physico-chemical properties of the nanomedicine but such modification affects also its efficacy and toxicity profiles. Ultimately, nanomedicines design results usually in a compromise between bioavailability, efficacy or toxicity. Here we propose a new approach to change the way nanomedicine are biodistributed, by priming the body to receive the treatment. This approach relies on the sequential administration of a nanoprimer before the nanomedicine. The nanoprimer is a nanoparticle designed to transiently occupy the main pathway responsible for the limited bioavailability of the nanomedicine. As such, the nanoprimer allows to redefine the bioavailability of the nanomedicine. Methods: For proof of concept we designed a liposomal nanoprimer with specific physico-chemical properties. Its biodistribution was evaluated by labelling with gold nanoparticles. 24h after intravenous (IV) administration on mice, gold quantification was performed on sampled organs by ICPMS. Toxicity evaluation was performed by 3 IV injections of nanoprimer spaced of 24h on mice followed by a one week follow up of body weight and clinical signs. Histological liver and spleen observations and transaminases titration were performed 1 and 7 days after last injection. Evaluation of the impact of nanoprimer on nanomedicines bioavailability was performed by in vivo follow up of a fluorescent nanomedicine IV injected 10min after nanoprimer IV injection. Tumor growth delay experiment was performed by IV administration of nanoprimer 10min before irinotecan loaded liposomes on mice xenografted with HT29 (colorectal adenocarcinoma) tumor model once the tumor reached 150mm3. Treatment was repeated one week later. Results: The liposomal nanoprimer presents a preferential hepatic accumulation. No signs of systemic or hepatic toxicity were observed with maximized dose of this nanoprimer. Nanomedicine bioavailability studies showed a transient increase of nanomedicine blood bioavailability correlated with a lower hepatic accumulation when combined to nanoprimer. Finally efficacy study showed that nanoprimer markedly enhanced anti-tumor efficacy of irinotecan loaded liposomes in the HT-29 model when compared to the nanomedicine alone. Body priming may benefit to a wide variety of existing products modulating their bioavailability and may open perspective to design new nanomedicines by decreasing the notion of compromise between bioavailability, efficacy and toxicity. Citation Format: Matthieu Germain, Laurence Poul, Marie-Edith Meyre, Marion Paolini, Francis Mpambani, Maxime Bergere, Agnes Pottier, Laurent Levy. Redefine nanomedicine products bioavailability to improve anti-tumor efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-072.

International audience; A new versatile hybrid nanocarrier has been designed using a " soft chemistry" synthesis, to efficiently encapsulate a photosensitizer - the protoporphyrin IX (Pp IX) - while preserving its activity intact in biological environment for advantageous use in photodynamic therapy (PDT). The synthesized Pp IX silica-based nanocarriers show to be spherical in shape and highly monodisperse with size extending from 10. nm up to 200. nm according to the synthesis procedure. Upon laser irradiation, the entrapped Pp IX shows to efficiently deliver reactive oxygen species (ROS) which are responsible for damaging tumor tissues. The ability of Pp IX silica-based nanocarriers to induce tumor cell death has been tested successfully in vitro. The stability of the Pp IX silica-based nanocarriers has been followed by UV-vis absorption and fluorescence emission in aqueous media and in 100% mouse serum media. The flexibility of the nanocarrier silica core has been examined as the key parameter to tune the Pp IX stability in biological environment. Indeed, an additional biocompatible inorganic surface coating performed on the Pp IX silica-based nanocarriers to produce an optimized bilayer coating demonstrates to significantly enhance the Pp IX stabilization in biological environments. Such versatile hybrid nanocarriers open new perspectives for PDT.

Background - Between 70 to 90% of patient have "cold" tumors, i.e. devoid or poorly infiltrated by immune cells, rendering inoperative their treatment by immune checkpoint inhibitors. To allow these patients to benefit from these therapies, it is fundamental to prime an antitumor immune response. Radiotherapy (RT) has demonstrated its ability to induce the immunogenic cell death (ICD), a crucial event allowing the priming of the antitumor immune response. Meanwhile, a new class of material with high electron density, hafnium oxide, was designed at the nanoscale (HfO2-NP) to efficiently absorb ionizing radiation and increase the radiation dose deposition from within the tumor cells and increase killing of cancer cells. Here, we compared the ability of HfO2-NP and RT to RT alone to kill cancer cells and induce immunogenic cell death. Methods - A panel of human and mouse cancer cell lines (mesenchymal and epithelial origin, radiosensitive and radioresistant) were treated or not with HfO2-NP, then irradiated by X-rays. Impact of the treatments on apoptosis and necrosis was assessed by FACS analysis (Annexin V/Propidium iodide). In addition, the production of the DAMPs characteristic of the ICD (secreted adenosine triphosphate (ATP), ecto-calreticulin (ecto-CALR), and extracellular High Mobility Group Box 1 (HMGB1)) and of two additional DAMPs (ecto-heat shock protein 70 (ecto-HSP70) and 90 (ecto-HSP90)) were determined. The ENLITEN ATP Assay system was used to measure the secreted-ATP. Ecto-(CRT, HSP70 and HSP90) were assessed by FACS analysis and HMGB1 by ELISA assay. Results - For all the tested cell lines treated with HfO2-NP and RT, a marked increase of apoptosis and necrosis was demonstrated, compared to cells treated with RT alone. In addition, higher levels of DAMPs (ecto-CRT, ecto-HSP70, ecto-HSP90, secreted ATP and extracellular HMGB1) were measured in the cancer cells treated with HfO2-NP and RT when compared to cancer cells exposed to RT. Conclusion - HfO2-NP has demonstrated its capacity to kill cancer cells more efficiently than radiotherapy alone. HfO2-NP, administered via a single intratumor injection, is currently evaluated in clinical trials including soft tissue sarcoma (phase II/III), head and neck, prostate, liver and rectum cancers (phase I) and would permit to improve the local control of tumors, a crucial parameter for the cure and survival of patients. Here, we further show that the superior ability of HfO2-NP and RT treatment to generate ICD would prime an antitumor immune response with more effectiveness than RT alone can do, converting the tumor into an actual in situ vaccine. Thus, this transformation by HfO2-NP of immunologically “cold” tumors into “hot” tumors would open a new avenue for the use of immune checkpoint inhibitors across oncology, particularly for non- and poor-responder patients. Citation Format: Julie Marill, Naeemunnisa Mohamed, Audrey Darmon, Laurent Levy, Elsa Borghi, Agnès Pottier, Sébastien Paris. Hafnium oxide nanoparticles with radiotherapy induce immunogenic cell death [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A30.

Protoporphyrin IX (Pp IX) silica nanoparticles, developed for effective use in photodynamic therapy (PDT), were explored in in vitro and in vivo models with the ambition to improve knowledge on the role of biological factors in the photodamage. Pp IX silica nanoparticles are found efficient at temperature with extreme metabolic downregulation, which suggest a high proportion of passive internalization. For the first time, clearance of silica nanoparticles on tumor cells is established. Cell viability assessment in six tumor cell lines is reported. In all tumor types, Pp IX silica nanoparticles are more efficient than free Pp IX. A strong fluorescence signal of reactive oxygen species generation colocalized with Pp IX silica nanoparticles, correlates with 100% of cell death. In vivo studies performed in HCT 116, A549 and glioblastoma multiforme tumors-bearing mice show tumor uptake of Pp IX silica nanoparticles with better tumor accumulation than the control alone, highlighting a high selectivity for tumor tissues. As observed in in vitro tests, tumor cell type is likely a major determinant but tumor microenvironment could more influence this differential time accumulation dynamic. The present results strongly suggest that Pp IX silica nanoparticles may be involved in new alternative local applications of PDT.

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.

This is a perspective on the current state of development of nanomedicines in Europe. The view is expressed that a much higher translational success rate could be achieved, with rewards for all stakeholders, if researchers understood the industrial decision points required for new drugs. Getting a drug through the clinic will not help patients unless it is developable by industry. This article is written in the hope that it will help researchers and SMEs to decide where they are in the established process, whether they are making progress and to determine what to do next. It attempts to map the early stages from ideation to first (time) in man (FIM). From the Clinical Editor The field of nanomedicine has come a long way in the past decade. The overall dream of any researcher in this field remains the realization of concept to clinical product. In this paper, the authors outlined for the readers, the underlying problems and actions that need to be done, so that current challenges can be solved.

Product development in the mobility industry is characterized by extreme time-to-market, high product complexity, cost pressure and many geographically dispersed stakeholders. Thus, efficient control mechanisms are necessary to manage a seemingly unmanageable project successfully and to achieve a strong finish. Digital mock-up (DMU) serves, as a central validation instrument in such a complex scenario, not only to visualize spatially the current status of the virtual product but also to evaluate the project’s progress. In conjunction with a high-variant product structure, as it is the case in modern vehicles, the use of DMU makes the check of the spatial consistency of the overall product possible, taking over what today’s CAD and PDM systems alone are not capable of. Taking the function of the product into account, the result is the so-called functional DMU (FDMU) which aims at facilitating the direct experience of functions on the virtual model in the overall context of the product. While DMU offers a visual straightforward human interface for control, DMU creation, calculation and processes can be automated well, so that the spatial test (collision check, assembly check) can be performed for all conceivable product variants in batch during the night). Nevertheless, human intervention is still required for the solution of design conflicts. Although all current problems are not yet solved in the context of DMU, leading PLM vendors do offer powerful tools to support the DMU process. Due to its central role in the development process DMU is subject of intensive research and development for speeding up the process and to increase accuracy.

This paper presents the use of nanoscale chemistry to synthesize a multilevel, hierarchically built nanoparticle, which we define as a nanoclinic, for targeted diagnostics and therapy. This nanoclinic, produced by multistep chemistry in a nanosize micelle, consists of a thin silica shell encapsulating magnetic (Fe2O3) nanoparticles and fluorescent dyes for enhanced contrast magnetic resonance and optical imaging and magnetic-induced cancer therapy. Furthermore, the surface of these prototype nanoclinics is functionalized with a biotargeting group, luteinizing hormone-releasing hormone (LH−RH). In the work reported here, the LH−RH targets receptor-specific cancer cells for utilization in imaging and investigation of biological effects. The structure and function of these nanoclinics have been characterized using electron and X-ray diffractions, transmission electron microscopy, atomic force and scanning electron microscopy and two-photon laser scanning microscopy. Targeting of the receptor-specific cells h...

Nanotechnology is rapidly expanding into the biomedical field. At the Institute for Lasers, Photonics and Biophotonics, research in nanotechnology has focused on the development of surface functionalized nanoparticles for diagnostics and targetted therapy. This technology provides a platform for the development of new imaging, diagnostic and therapeutic modalities. For bioimaging and diagnostics, nanoparticles are fabricated containing rare-earth ions which exhibit two-photon, anti-stokes luminescence by frequency up-converting infrared to visible light. We have successfully prepared the phosphor containing nanoparticles having a size ∼25 nm with a silica shell around it which helps in aqueous dispersabilty, inhibits water quenching with nanophosphors and allows functionalization for covalent binding of bioprobes for targeting. The coupling of specific peptides, proteins or nucleic acid sequences to the silica shell will allow for the selective detection of biological entities and will have applications i...

Major advances in nanotechnology and cancer biology have occurred throughout the last 30 years. The concept of “magnetic nanoclinic” demonstrated here, combines these advances in cancer and nanotechnology forming the basis for a new generation of non-invasive anti-cancer tools. This nanoclinic is a multifunctional nanoparticle (< 50 nm) that has been fabricated to selectively enter, provide optical imaging capability and administer externally controled therapy from within the cell. The magnetic nanoclinics were designed with an Fe2O3 core for magnetocytolysis using a DC magnetic field and a two-photon fluorescent probe to aid in optical tracking. Surface labeling with the peptide analog of luteinizing hormone releasing hormone (LH-RH) provides targetting to specific cancer cell types. These nanoclinics demonstrate the ability to selectively lyse cells expressing LH-RH receptors upon exposure to a DC magnetic field similar to that used for magnetic resonance imager in diagnostic settings. This study demonstrates the fabrication of and in vitro feasibility of nanoclinics as a non-invasive approach to the treatment of selected cancers using a DC magnetic field.

Background Hafnium oxide, NBTXR3 nanoparticles were designed for high dose energy deposition within cancer cells when exposed to ionizing radiation. The purpose of this study was to assess the possibility of predicting in vitro the biological effect of NBTXR3 nanoparticles when exposed to ionizing radiation. Methods Cellular uptake of NBTXR3 nanoparticles was assessed in a panel of human cancer cell lines (radioresistant and radiosensitive) by transmission electron microscopy. The radioenhancement of NBTXR3 nanoparticles was measured by the clonogenic survival assay. Results NBTXR3 nanoparticles were taken up by cells in a concentration dependent manner, forming clusters in the cytoplasm. Differential nanoparticle uptake was observed between epithelial and mesenchymal or glioblastoma cell lines. The dose enhancement factor increased with increase NBTXR3 nanoparticle concentration and radiation dose. Beyond a minimum number of clusters per cell, the radioenhancement of NBTXR3 nanoparticles could be estimated from the radiation dose delivered and the radiosensitivity of the cancer cell lines. Conclusions Our preliminary results suggest a predictable in vitro biological effect of NBTXR3 nanoparticles exposed to ionizing radiation.

Since the discovery of cisplatin about 40 years ago, the design of innovative metal-based anticancer drugs is a growing area of research. Transition metal coordination complexes offer potential advantages over the more common organic-based drugs, including a wide range of coordination number and geometries, accessible redox states, tunability of the thermodynamics and kinetics of ligand substitution, as well as a wide structural diversity. Metal-based substances interact with cell molecular targets, affecting biochemical functions resulting in cancer cell destruction. Radionuclides are another way to use metals as anticancer therapy. The metal nucleus of the unstable radionuclide becomes stable by emitting energy. The biological effect in different tissues is obtained by the absorption of this energy from the radiation emitted by the radionuclide, the principal target generally agreed for ionizing radiations being DNA. A new area of clinical research is now emerging using the same experimental metal elements, but in a radically different manner: metals and metal oxides used as crystalline nanosized particles. In this field, man-made functionalized nanoparticles of high electron density and well-defined size and shape offer the possibility of entering cancer cells and depositing high amounts of energy in the tumor only when exposed to ionizing radiations (on/off activity). These nanoparticles, such as hafnium oxide engineered as 50 nm-sized spheres, functionalized with a negative surface (NBTXR3 nanoparticles), have been developed as selective radioenhancers, which represents a breakthrough approach for the local treatment of solid tumors. The properties of NBTXR3 nanoparticles, their chemistry, size, shape and surface charge, have been designed for efficient tumor cell uptake. NBTXR3 brings a physical mode of action, that of radiotherapy, within the cancer cells themselves. Physicochemical characteristics of NBTXR3 have demonstrated a very promising benefit-risk ratio for human healthcare across a broad non-clinical program. NBTXR3 has entered clinical development in therapy of advanced soft tissue sarcomas and head and neck cancer.

Multifunctional nanostructured materials and composites are of considerable interest for photonics, optoelectronics and biophotonics. This paper will focus on three topics. In the first part of the paper, we will focus on silica encapsulated multifunctional nanoparticles. These particles show enhanced optical properties as well as photo, chemical and thermal stability. In the second part of the paper, we investigate the Er3+ sol-gel multicomponent silica glass prepared with nanostructure control for 1.55 μm amplification. These glasses demonstrate the longest reported lifetime in sol-gel glasses to date, which we attribute to the reduction of the hydroxyl content in the glass. The third part of the paper discusses our work on photonic crystals.

The magnetic-field-induced 3D ordered phase of the two-leg spin ladder Cu2(C5H12N2)2Cl4 has been probed through measurements of 1H NMR spectra and 1/T1 in the temperature range 70 mK-1.2 K. The second order transition line T(c)(H) has been determined between H(c1) = 7.52 T and H(c2) = 13.5 T and varies as (H-H(c1))(2/3) close to H(c1). From the observation of anomalous shifts and a crossover in 1/T1 above T(c), the mechanism of the 3D transition is argued to be magnetoelastic as in spin-Peierls chains, here involving a displacement of the protons along the longitudinal exchange ( J( parallel)) path.

We report the preparation, luminescent properties, and bioimaging applications of a novel zinc sulfide (core)-two-photon dye−silica (shell) multilayered heterostructure. The method utilizes reverse micelles synthesis involving multistep reactions as a result of which composite nanoparticles having different sizes and morphology can be obtained. The size of these composite nanoparticles is typically 15−30 nm. An increase in the luminescence intensity (∼70 times higher) and in fluorescence lifetime is observed for the dye encapsulated within the silica nanobubble. Photobleaching results indicate that the dye is truly encapsulated and the silica shell provides a barrier to penetration of oxygen, thereby making the dye more photostable. The application of these particles as nanoprobes for bioimaging of cells using two-photon laser scanning microscopy is also presented.

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.

In this Letter, a model of a Cd1-yMnyS nanocrystal is proposed to explain the appearance of manganese ions isolated in the tetrahedral site, at relatively high composition, whereas magnetic interactions markedly increase in the nanosized range compared to the bulk phase.

Specific heat ($C_V$) measurements in the spin-1/2 Cu$_2$(C$_2$H$_{12}$N$_2$)$_2$Cl$_4$ system under a magnetic field up to $H=8.25 T$ are reported and compared to the results of numerical calculations based on the 2-leg antiferromagnetic Heisenberg ladder. While the temperature dependences of both the susceptibility and the low field specific heat are accurately reproduced by this model, deviations are observed below the critical field $H_{C1}$ at which the spin gap closes. In this Quantum High Field phase, the contribution of the low-energy quantum fluctuations are stronger than in the Heisenberg ladder model. We argue that this enhancement can be attributed to dynamical lattice fluctuations. Finally, we show that such a Heisenberg ladder, for $H>H_{C1}$, is unstable, when coupled to the 3D lattice, against a lattice distortion. These results provide an alternative explanation for the observed low temperature ($T_C\sim 0.5K$ -- $0.8K$) phase (previously interpreted as a 3D magnetic ordering) as a new type of incommensurate gapped state.

In this paper, we present, for the first time, the magnetic properties of Cd1-yMnyS nanocrystals of average size (4 nm) at various compositions, y. We demonstrate that the Mn−Mn interactions are markedly enhanced compared to the bulk material. As in the bulk phase, the photoluminescence and the EPR hyperfine structure, both attributed to isolated Mn2+ ions in a tetrahedral coordination, behave similarly with increasing composition. At the opposite of the bulk phase, isolated Mn2+ ions are observed for a rather large composition (y = 0.08) in nanocrystals. We attempt to relate the change of the band gap with composition with the various manganese interactions.

In a magnetic field, spin-ladders undergo two zero-temperature phase transitions at the critical fields Hc1 and Hc2. An experimental review of static and dynamical properties of spin-ladders close to these critical points is presented. The scaling functions, universal to all quantum critical points in one-dimension, are extracted from (a) the thermodynamic quantities (magnetization) and (b) the dynamical functions (NMR relaxation). A simple mapping of strongly coupled spin ladders in a magnetic field on the exactly solvable XXZ model enables to make detailed fits and gives an overall understanding of a broad class of quantum magnets in their gapless phase (between Hc1 and Hc2). In this phase, the low temperature divergence of the NMR relaxation demonstrates its Luttinger liquid nature as well as the novel quantum critical regime at higher temperature. The general behaviour close these quantum critical points can be tied to known models of quantum magnetism.

We present an extensive NMR study of the spin-1/2 antiferromagnetic Heisenberg ladder $\mathrm{Cu}{}_{2}({\mathrm{C}}_{5}{\mathrm{H}}_{12}{\mathrm{N}}_{2}{)}_{2}\mathrm{Cl}{}_{4}$ in a magnetic field range 4.5--16.7 T. By measuring the proton NMR relaxation rate $1/{T}_{1}$ and varying the magnetic field around the critical field ${H}_{c1}\phantom{\rule{0ex}{0ex}}=\phantom{\rule{0ex}{0ex}}\ensuremath{\Delta}/g{\ensuremath{\mu}}_{B}\ensuremath{\approx}7.5\mathrm{T}$, we have studied the transition from a gapped spin liquid ground state to a gapless magnetic regime which can be described as a Luttinger liquid. We identify an intermediate regime $T\ensuremath{\ge}|{H\ensuremath{-}H}_{c1}|$, where the spin dynamics is (possibly) only controlled by the $T\phantom{\rule{0ex}{0ex}}=\phantom{\rule{0ex}{0ex}}0$ critical point ${H}_{c1}$.

In this paper we demonstrate that the use of colloidal assemblies permits to control independently the size and composition of Cd 1− y Mn y S nanosized particles. As expected, for a given composition, the increase in the band-edge energy with decreasing the particle size is observed and attributed to a quantum size effect. For a similar average particle size, the band gap does not vary linearly when manganese concentration increases. The minimum is more pronounced and its depth increases with decreasing the particle size. This is attributed to a quantum size effect and due to strong interactions between manganese ions and the conduction and valence bands electrons. For similar size of nanocrystals, the photoluminescence due to isolated Mn 2+ ions in Cd 1− y Mn y S nanoclusters is observed when the particles are aged and the CdS trap emission is observed immediately after the synthesis. The most important parameter in order to observe the Mn 2+ ions luminescence is the aging time of the particles and not a quantum size effect as claimed previously.

Absorption and photoluminescence spectroscopic measurements are presented for particles with sizes from 2 to 4 nm, composition from y = 0 to 0.3,where y is given by Cd1-yMnyS, and different preparation modes. No monotonous variation of bandgap energy with increasing composition is observed. The depth of the minimum increases with decreasing particle size. This is attributed to a marked increase in the interactions between the Mn2+ d electrons and the valence and conduction band electrons. Mn2+ photoluminescence is observed at 77 K, when the particles are aged in the solution. Otherwise only the trap emissions due to CdS defect states are seen. Certain preparation modes favor Mn2+ photoluminescence at room temperature.

The ${}^{1}\mathrm{H}$ hyperfine shift $K$ and NMR relaxation rate ${T}_{1}^{\ensuremath{-}1}$ have been measured as a function of temperature in the $S\phantom{\rule{0ex}{0ex}}=\phantom{\rule{0ex}{0ex}}1/2$ Heisenberg antiferromagnetic ladder compound ${\mathrm{Cu}}_{2}({\mathrm{C}}_{5}{\mathrm{H}}_{12}{\mathrm{N}}_{2}{)}_{2}{\mathrm{Cl}}_{4}$. The presence of a spin gap $\ensuremath{\Delta}\ensuremath{\simeq}{J}_{\ensuremath{\perp}}{\ensuremath{-}J}_{\ensuremath{\parallel}}$ in this strongly coupled ladder ( ${J}_{\ensuremath{\parallel}}l{J}_{\ensuremath{\perp}}$) is supported by the $K$ and ${T}_{1}^{\ensuremath{-}1}$ results. By comparing ${T}_{1}^{\ensuremath{-}1}$ at two different ${}^{1}\mathrm{H}$ sites, we infer the evolution of the spectral functions ${S}_{z}(q,{\ensuremath{\omega}}_{n})$ and ${S}_{\ensuremath{\perp}}(q,{\ensuremath{\omega}}_{n})$. When the gap is significantly reduced by the magnetic field, two different channels of nuclear relaxation, specific to gapped antiferromagnets, are identified and are in agreement with theoretical predictions.

We study the magnetization of a Heisenberg spin ladder using exact diagonalization techniques, finding three distinct magnetic phases. We consider the results in relation to the experimental behaviour of the new copper compound Cu_2(C_5H_{12}N_2)_2Cl_4 and deduce that the compound is well described by such a model with a ratio of `chain' to `rung' bond strengths (J/J^\prime) of the order of 0.2, consistent with results from the magnetic susceptibility. The effects of temperature, spin impurities and additional diagonal bonds are presented and we give evidence that these diagonal bonds are indeed of a ferromagnetic nature.