Decoration of squalenoyl-gemcitabine nanoparticles with squalenyl-hydroxybisphosphonate for the treatment of bone tumors

Therapeutic perspectives of bone tumors such as osteosarcom are main restricted due to the inefficacy of current treatments. We propose here the construction of a novel anticancers qualene-based nanomedicine with bone affinity and retention capacity. A squalenyl-hydroxybisphosphonate molecule was synthetized by chemical conjugation of a 1-hydroxyl-1,1-bi-sphosphonatemoiety to the squalenechain. This amphiphilic compound was inserted onto squalenoyl-gemcitabinenano-particles using the nanoprecipitation method. The co-assemblyled to nanoconstructsof 75 nm, with different morphology and colloidal properties. The presence of squalenyl-hydroxybi-sphosphonate enhanced the nanoparticles binding affinity for hydroxyapatite,a mineral present in the bone. Moreover, the in vitro anticancer activity was preserved when tested in commercial and patient-treated derived pedia tricoste osarcomacells. Furtherin vivo studies will shed lighton the potential of these nano medicines for the treatment of bones arcomas

In Vivo FRET Imaging to Predict the Risk Associated with Hepatic Accumulation of Squalene-Based Prodrug Nanoparticles.

Förster resonance energy transfer (FRET) is used here for the first time to monitor the in vivo fate of nanoparticles made of the squalene-gemcitabine prodrug and two novel derivatives of squalene with the cyanine dyes 5.5 and 7.5, which behave as efficient FRET pair in the NIR region. Following intravenous administration, nanoparticles initially accumulate in the liver, then they show loss of their integrity within 2 h and clearance of the squalene bioconjugates is observed within 24 h. Such awareness is a key prerequisite before introduction into clinical settings.journal article2018 Feb2017 11 30importedSupporting information : librement accessible sur le site de l'éditeur

An atlas of over 90.000 conserved noncoding sequences provides insight into crucifer regulatory regions

Despite the central importance of noncoding DNA to gene regulation and evolution, understanding of the extent of selection on plant noncoding DNA remains limited compared to that of other organisms. Here we report sequencing of genomes from three Brassicaceae species (Leavenworthia alabamica, Sisymbrium irio and Aethionema arabicum) and their joint analysis with six previously sequenced crucifer genomes. Conservation across orthologous bases suggests that at least 17% of the Arabidopsis thaliana genome is under selection, with nearly one-quarter of the sequence under selection lying outside of coding regions. Much of this sequence can be localized to approximately 90,000 conserved noncoding sequences (CNSs) that show evidence of transcriptional and post-transcriptional regulation. Population genomics analyses of two crucifer species, A. thaliana and Capsella grandiflora, confirm that most of the identified CNSs are evolving under medium to strong purifying selection. Overall, these CNSs highlight both similarities and several key differences between the regulatory DNA of plants and other species

Combinatorial nanomedicine made of squalenoyl-gemcitabine and edelfosine for the treatment of pediatric cancer

Chemotherapy protocols for childhood cancers are still problematic due to the high toxicity associated with chemotherapeutic agents, and incorrect dosing regimens extrapolated from adults. Nanotechnology has demonstrated significant ability to reduce toxicity of anticancer compounds. Improvement in the therapeutic index of cytostatic drugs, makes this strategy an alternative to common chemotherapy in adults. Among anticancer nanomedicines, squalenoyl nanocomposites have obtained encouraging outcomes in a great variety of tumors. The prodrug squalenoyl-gemcitabine was chosen in this study to construct a novel multidrug nanosystem in combination with edelfosine, an alkyl-lysophopholipid with proven anticancer activity. Given their amphiphilic nature, it was hypothesized that both anticancer compounds, with complementary molecular targets, could lead to the formation of a new multitherapy nanomedicine. Nanoassemblies were formulated by nanoprecipitation method and characterized by dynamic light scattering, transmission electron microscopy, X-ray photoelectron spectroscopy and UHPLC tandem mass spectroscopy. It was observed that these molecules spontaneously self-assembled as stable and monodisperse nanoassemblies of 51 ± 1 nm in a surfactant/polymer free-aqueous suspension. Compared to squalenoyl-gemcitabine nanoassemblies, the combination of squalenoyl-gemcitabine with edelfosine resulted in smaller particle size and a new supramolecular conformation, with higher stability and drug content. On the other hand, squalenoyl-gemcitabine/edelfosine nanoassemblies were found to be capable of intracellular translocation in patient-derived metastatic pediatric osteosarcoma cells (531M) and showed a better antitumor profile in vitro than squalenoyl-gemcitabine nanoassemblies in neuroblastoma (SH-SY5Y) and pediatric osteosarcoma (U2-OS) cell lines. The intravenous administration of this combinatorial nanomedicine in mice exhibited a controlled release behavior of gemcitabine and diminished edelfosine plasma peak concentrations. For their in vivo pre-clinical assessment in an orthotopic osteosarcoma tumor model, c-Fos overexpressing P1.15 cells were intratibially injected in athymic nude mice. In comparison with the control groups, the combinatorial nanomedicine was found to decrease the primary tumor growth kinetics and to reduce the number of lung metastases. Our findings support the candidature of squalenoyl-gemcitabine/edelfosine nanoassemblies as a potential pediatric cancer therapy. Improving the quality of life of cancer patients is essential, particularly in the case of the pediatric population. In these studies, we successfully designed squalenoyl-gemcitabine/edelfosine nanoassemblies of 50 nm, which proved to be safe and efficacious in a murine osteosarcoma model. The findings gathered in this thesis shed light on the promising future of combinatory nanomedicine to replace current cancer treatments