Agnès Pottier

Synthesis of brookite TiO2 nanoparticlesby thermolysis of TiCl4 in strongly acidic aqueous media

Nanometric particles of titania, brookite and rutile polymorphs were synthesised by thermolysis of TiCl4 in concentrated HCl solutions. The Cl∶Ti molar ratio seems to be the key factor in determining the crystalline phases and their relative proportions as well as the particle size and a large proportion of brookite can be obtained under specific conditions. The complex Ti(OH)2(Cl)2(OH2)2 seems to be the precursor of the brookite phase. The presence of chloride ions is also necessary to stabilise brookite in suspension. Depending on the acidity and the ageing conditions, different morphologies of brookite nanoparticles are obtained, namely spheroidal particles or platelets. Stable sols of pure brookite are obtained by peptization of the solid phase.

Size tailoring of TiO2 anatase nanoparticles in aqueous medium and synthesis of nanocomposites. Characterization by Raman spectroscopy

Nanoparticles of anatase with mean size in the range 5–10 nm were prepared by precipitation of TiCl4 in aqueous medium in the range 2 ≤ pH ≤ 6. Hydroxylation of TiCl4 at room temperature leads instantaneously to an amorphous titanium oxyhydroxide phase which crystallizes as anatase upon aging at 60 °C in suspension. Small amounts of brookite or rutile are concurrently obtained depending on the acidity. The size of anatase particles was characterized by X-ray diffraction, electron microscopy and Raman spectroscopy. The latter was also used to determine the particle size and to characterize the crystallinity of particles through the phonon confinement effect. The particle size, dependent on the acidity, is closely related to the electrostatic surface charge density of particles. The size variation was interpreted as resulting from a lowering of the interfacial tension due to the protonation of particle surface groups. Composite materials were synthesized by polymerisation of silica in aqueous sols of anatase. The dispersed anatase nanoparticles are stable against the transformation to rutile up to 1000 °C.

Size tailoring of oxide nanoparticles by precipitation in aqueous medium. A semi-quantitative modelling

Chemistry in aqueous solution is an easy and versatile method to form nanosized metal oxide particles. Considering our previous results on magnetite Fe3O4, anatase TiO2, brucite Mg(OH)2, and boehmite γ-AlOOH, we show that the strict control of the physicochemical conditions of the precipitation, essentially the acidity and ionic strength in the absence of complexing species, enables the tailoring of the particle size in the range 2–15 nm and, in some cases, of their morphology. We show that the variations in size and/or shape are tightly related to the variation of the electrostatic surface charge density of the particles, which induces a variation of the oxide-solution interfacial tension, and, consequently, a decrease of the surface energy. Such an effect enables the control of the surface area of the system. A semi-quantitative model is presented, which accounts for the effects observed for particles isotropic or anisotropic in shape.

Nanoscale radiotherapy with hafnium oxide nanoparticles

AIM There is considerable interest in approaches that could improve the therapeutic window of radiotherapy. In this study, hafnium oxide nanoparticles were designed that concentrate in tumor cells to achieve intracellular high-energy dose deposit. MATERIALS & METHODS Conventional methods were used, implemented in different ways, to explore interactions of these high-atomic-number nanoparticles and ionizing radiation with biological systems. RESULTS Using the Monte Carlo simulation, these nanoparticles, when exposed to high-energy photons, were shown to demonstrate an approximately ninefold radiation dose enhancement compared with water. Importantly, the nanoparticles show satisfactory dispersion and persistence within the tumor and they form clusters in the cytoplasm of cancer cells. Marked antitumor activity is demonstrated in human cancer models. Safety is similar in treated and control animals as demonstrated by a broad program of toxicology evaluation. CONCLUSION These findings, supported by good tolerance, provide the basis for developing this new type of nanoparticle as a promising anticancer approach in human patients.

Pp IX Silica Nanoparticles Demonstrate Differential Interactions with In Vitro Tumor Cell Lines and In Vivo Mouse Models of Human Cancers

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.

Hafnium oxide nanoparticles: toward an in vitro predictive biological effect?

BackgroundHafnium 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.MethodsCellular 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.ResultsNBTXR3 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.ConclusionsOur preliminary results suggest a predictable in vitro biological effect of NBTXR3 nanoparticles exposed to ionizing radiation.

MRI contrast variation of thermosensitive magnetoliposomes triggered by focused ultrasound: a tool for image-guided local drug delivery

Improved drug delivery control during chemotherapy has the potential to increase the therapeutic index. MRI contrast agent such as iron oxide nanoparticles can be co-encapsulated with drugs in nanocarrier liposomes allowing their tracking and/or visualization by MRI. Furthermore, the combination of a thermosensitive liposomal formulation with an external source of heat such as high intensity focused ultrasound guided by MR temperature mapping allows the controlled local release of the content of the liposome. MRI-guided high-intensity focused ultrasound (HIFU), in combination represents a noninvasive technique to generate local hyperthermia for drug release. In this study we used ultrasmall superparamagnetic iron oxide nanoparticles (USPIO) encapsulated in thermosensitive liposomes to obtain thermosensitive magnetoliposomes (TSM). The transverse and longitudinal relaxivities of this MRI contrast agent were measured upon TSM membrane phase transition in vitro using a water bath or HIFU. The results showed significant differences for MRI signal enhancement and relaxivities before and after heating, which were absent for nonthermosensitive liposomes and free nanoparticles used as controls. Thus, incorporation of USPIO as MRI contrast agents into thermosensitive liposomes should, besides TSM tumor accumulation monitoring, allow the visualization of TSM membrane phase transition 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 drug therapeutic index.

The future of nanosized radiation enhancers

Radiotherapy has a universal and predictable mode of action, that is, a physical mode of action consisting of the deposit of a dose of energy in tissues. Tumour cell damage is proportional to the energy dose. However, the main limitation of radiotherapy is the lack of spatial control of the deposition of energy, that is, it penetrates the healthy tissues, damages them and renders unfeasible delivery of an efficient energy dose when tumours are close to important anatomical structures. True nanosized radiation enhancers may represent a disruptive approach to broaden the therapeutic window of radiation therapy. They offer the possibility of entering tumour cells and depositing high amounts of energy in the tumour only when exposed to ionizing radiations (on/off activity). They may unlock the potential of radiation therapy by rendering the introduction of a greater energy dose, exactly within the tumour structure without passing through surrounding tissues feasible. Several nanosized radiation enhancers have been studied in in vitro and in vivo models with positive results. One agent has received the authorization to conduct clinical trials for human use. Opportunities to improve outcomes for patients receiving radiotherapy, to create new standards of care and to offer solutions to new patient populations are looked over here.

Nano-sized cytochrome P450 3A4 inhibitors to block hepatic metabolism of docetaxel

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 bio-compatible 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 24 hours 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 63 nm, functionalized with galactosamine, showed efficient in vitro 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).

Priming the body to receive the therapeutic agent to redefine treatment benefit/risk profile

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.