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

Combined strategy based on pre-activated analogs of oxazaphosphorines for increased therapeutic index and immune modulation

Oxazaphosphorines (Oxaza) represented by cyclophosphamide (CPA) and ifosfamide (IFO) are still the corner stone of several polychemotherapy protocols as they are widely indicated in the treatment of numerous cancer from soft tissue sarcomas to lymphomas and immune-related diseases. However, Oxaza are prodrugs requiring cytochrome (CYP) P450 bioactivation responsible of limiting adverse effects. In the case of IFO, bioactivation leads to a low release of 4-OH-IFO (10%), which generates the active nitrogen mustard displaying DNA cross-links. Associated toxicities of IFO due to acrolein, (urotoxicity) and to chloroacetaldehyde (neuro and nephrotoxicity) have been described. Thus, increasing IFO therapeutic index could be of major interest. To circumvent these toxicities, our team has designed new pre-activated IFO analogs to avoid CYP bioactivation (Skarbek et al J Med Chem 2015). Among these analogues some have the ability to self-assemble as nanoassemblies (NAs), the others can be encapsulated within nano-lipid capsules (NLCs). These new drug delivery systems (DDS) can take advantage of passive targeting, as stealthiness of these DDS can be provided by PEGylation by using Cholesterol-polyethylene glycol or the use of surfactant. These DDS can also be functionalized by appropriate monoclonal antibodies leading to multi stage DDS with active targeting properties. Regarding CPA, it has been shown and described in literature that low doses of CPA enhance the immunity by promoting differentiation of CD4⁺ cell toward Th1. As IFO is isomeric form of CPA, it was assumed that IFO could also have such properties. Studies on immunocompetent MCA205 mouse model, an immunogenic fibrosarcoma mouse model, demonstrate a dose-dependent immunomodulation of IFO towards a modulation of the secretion of IFNy, IL-17A and IL-6 cytokines. The ongoing experiments on mouse model depleted in CD4⁺ T cells and CD8⁺ T cells show the antitumor efficacy of IFO 150mg/kg on these immune cells in tumor regression. Both strategies could lead to the design of nano-immuno-conjugates (NICs) which could benefit of the immunomodulatory effects of X-Oxaza combined to their antiproliferative properties targeted through immune checkpoint antibodies. These new functionalized DDS may provide a useful strategy to give specificity to active drugs used for many years in clinical practice. Both DDS could be grafted with mAbs which could lead to a new family of DDS aiming to combine antiproliferative and immunomodulatory properties for a dual antitumoral action Citation Format: Julia Delahousse, Charles Skarbek, Valentine Gauthier, M Desbois, Emilie Roger, C. Pioche-Durieu, M. Rivard, D. Desmaële, T. Martens, E. LeCam, Jean-Pierre Benoit, P. Couvreur, Nathalie Chaput-Gras, Angelo Paci. Combined strategy based on pre-activated analogs of oxazaphosphorines for increased therapeutic index and immune modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2195. doi:10.1158/1538-7445.AM2017-219

A relevant in vitro rat model for the evaluation of blood-brain barrier translocation of nanoparticles

Poly(MePEG2000cyanoacrylate-co-hexadecylcyanoacrylate) (PEG-PHDCA) nanoparticles have demonstrated their capacity to reach the rat central nervous system after intravenous injection. For insight into the transport of colloidal systems across the blood-brain barrier (BBB), we developed a relevant in vitro rat BBB model consisting of a coculture of rat brain endothelial cells (RBECs) and rat astrocytes. The RBECs used in our model displayed and retained structural characteristics of brain endothelial cells, such as expression of P-glycoprotein, occludin and ZO-1, and immunofluorescence studies showed the specific localization of occludin and ZO1. The high values of transendothelial electrical resistance and low permeability coefficients of marker molecules demonstrated the functionality of this model. The comparative passage of polyhexadecylcyanoacrylate and PEG-PHDCA nanoparticles through this model was investigated, showing a higher passage of PEGylated nanoparticles, presumably by endocytosis. This result was confirmed by confocal microscopy. Thanks to a good in vitro/in vivo correlation, this rat BBB model will help in understanding the mechanisms of nanoparticle translocation and in designing new types of colloidal carriers as brain delivery systems

JOURNAL OF MICROMECHANICS AND MICROENGINEERING

A resonant structure designed for probing the elastic properties of suspension and adherent cells in liquid environments This article has been downloaded from IOPscience. Please scroll down to see the full text article

Revisiting absorption and electronic circular dichroism spectra of cholesterol in solution: A joint experimental and theoretical study

International audienceCholesterol is doubtless one of the most studied bio-molecules, which unfortunately features low emitting properties, precluding its in vivo study by fluorescence experiments. The design of fluorescent analogues of cholesterol is thus an appealing challenge in biochemistry, which simultaneously requires minor changes in its chemical structure (to retain main biological properties) and considerable enhancement of light emission. To this aim, the photochemical behaviour of the native molecule has to be deeply understood. In this work, we focused our attention on the electronic absorption of cholesterol in several common organic solutions, combining experimental (through ultraviolet-visible and electronic circular dichroism spectroscopy) and theoretical approaches (at the time-dependent density functional theory level) in order to solve the important discrepancies previously reported in the literature on the maximum absorption wavelengths and on the nature (Rydberg and/or π → π*) of the associated electronic transition

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