Nanoparticles loaded with ferrocenyl tamoxifen derivatives for breast cancer treatment.

International audienceFor the first time, two organometallic triphenylethylene compounds (Fc-diOH and DFO), with strong antiproliferative activity in breast cancer cells, but insoluble in biological fluids, were incorporated in two types of stealth nanoparticles (NP): PEG/PLA nanospheres (NS) and nanocapsules (NC). Their physicochemical parameters were measured (size, zeta potential, encapsulation and loading efficiency), and their biological activity was assessed. In vitro drug release after high dilution of loaded NPs was measured by estradiol binding competition in MELN cells. The influence of the encapsulated drugs on the cell cycle and apoptosis was studied by flow cytometry analyses. Notwithstanding potential drug adsorption at the NP surface, Fc-diOH and DFO were incorporated efficiently in NC and NS, which slowly released both compounds. They arrested the cell cycle in the S-phase and induced apoptosis, whose activity is increased by loaded NS. A decrease in their antiproliferative activity by the antioxidant alpha-tocopherol indicated that reactive oxygen species (ROS) may be involved. Therefore, nanosystems, containing for the first time a high load of anticancer organometallic triphenylethylenes, have been developed. Their small size and delayed drug release, combined with their enhanced apoptotic potential, are compatible with an increased persistence in the blood and a promising antitumour activity

Design of engineered cyclodextrin derivatives for spontaneous coating of highly porous metal-organic framework nanoparticles in aqueous media

Nanosized metal-organic frameworks (nanoMOFs) MIL-100(Fe) are highly porous and biodegradable materials that have emerged as promising drug nanocarriers. A challenging issue concerns their surface functionalization in order to evade the immune system and to provide molecular recognition ability, so that they can be used for specific targeting. A convenient method for their coating with tetraethylene glycol, polyethylene glycol, and mannose residues is reported herein. The method consists of the organic solvent-free self-assembly on the nanoMOFs of building blocks based on beta-cyclodextrin facially derivatized with the referred functional moieties, and multiple phosphate groups to anchor to the nanoparticles’ surface. The coating of nanoMOFs with cyclodextrin phosphate without further functional groups led to a significant decrease of macrophage uptake, slightly improved by polyethylene glycol or mannose-containing cyclodextrin phosphate coating. More notably, nanoMOFs modified with tetraethylene glycol-containing cyclodextrin phosphate displayed the most effcient “stealth” effect. Mannose-coated nanoMOFs displayed a remarkably enhanced binding affnity towards a specific mannose receptor, such as Concanavalin A, due to the multivalent display of the monosaccharide, as well as reduced macrophage internalization. Coating with tetraethylente glycol of nanoMOFs after loading with doxorubicin is also described. Therefore, phosphorylated cyclodextrins o er a versatile platform to coat nanoMOFs in an organic solvent-free, one step manner, providing them with new biorecognition and/or “stealth” properties

Intrinsic antibacterial activity of nanoparticles made of β-cyclodextrins potentiates their effect as drug nanocarriers against tuberculosis

Multi-drug-resistant tuberculosis (TB) is a major public health problem, concerning about half a million cases each year. Patients hardly adhere to the current strict treatment consisting of more than 10 000 tablets over a 2-year period. There is a clear need for efficient and better formulated medications. We have previously shown that nanoparticles made of cross-linked poly-β-cyclodextrins (pβCD) are efficient vehicles for pulmonary delivery of powerful combinations of anti-TB drugs. Here, we report that in addition to being efficient drug carriers, pβCD nanoparticles are endowed with intrinsic antibacterial properties. Empty pβCD nanoparticles are able to impair Mycobacterium tuberculosis (Mtb) establishment after pulmonary administration in mice. pβCD hamper colonization of macrophages by Mtb by interfering with lipid rafts, without inducing toxicity. Moreover, pβCD provoke macrophage apoptosis, leading to depletion of infected cells, thus creating a lung microenvironment detrimental to Mtb persistence. Taken together, our results suggest that pβCD nanoparticles loaded or not with antibiotics have an antibacterial action on their own and could be used as a carrier in drug regimen formulations effective against TB.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Fractionnement par pervaporation de mélanges liquides hydro-organiques partiellement miscibles : mise en évidence du rôle de la structure cristalline des membranes denses sur leurs propriétés de transport

We have studied the pervaporation properties of different liquid mixtures presenting a miscibility gap. Depending on inner polymer interactions, we defined an “ideal” and a particular bahaviour, and we chose to focus on one membrane of each category : Cellulose Acetate (AC) and Poly(vinyl Alcohol) (PVA), among those widely used in industry. We show that AC swells the same way in both phases in thermodynamic equilibrium, whereas PVA does not. Concentration polarization is the only mean to specifically modify one of the partial fluxes. PVA is a typical semicrystalline polymer, whose structure governs the proportions of the three possible states of soaked water. After a review of the properties ruled by the amount of crystallites in the polymer, we have build a qualitative model devoted to the permeation and swelling properties in two phases in a steady thermodynamic state. We then came to a quantitative model of the pervaporation process using PVA membranes. The result of this study is the fact that soacked water of an absorbent polymer defines its behavior when used as a membrane to pervaporate a hydro-organic mixtureNous avons étudié les particularités que manifestent, en pervaporation, les mélanges binaires dont les deux constituants ne sont pas miscibles en toute proportion. Selon la nature des interactions qui s'exercent à l'intérieur du système examiné, nous avons distingué un comportement idéal auquel s'opposent quelques cas particuliers. Nous approfondissons l'étude en choisissant une membrane idéale (acétate de cellulose) et une membrane au comportement particulier (alcool polyvinylique), parmi celles qui se rapprochent le plus des matériaux utilisés à l'échelle industrielle en pervaporation. Nous montrons que l'acétate de cellulose gonfle de manière identique dans deux phases liquides en équilibre thermodynamique. La polarisation de concentration en phase liquide est l'unique raison pour laquelle les flux partiels pourraient être différents en pervaporation. L'alcool polyvinylique est, lui, un exemple typique de matériau semicristallin. Nous avons distingué trois états différents du liquide absorbe, dont les proportions respectives dépendent de la cristallinité du polymère. Apres avoir identifié l'influence de la structure fine (cristalline) sur plusieurs autres de ses propriétés, nous avons étudié la conséquence de l'absorption d'eau sur la mobilité de ses chaines. Le modèle qualitatif élaboré à partir de l'ensemble des données permet de mieux comprendre les propriétés de perméation et de gonflement dans deux phases en équilibre thermodynamique. Finalement, nous établissons un modèle quantitatif pour la pervaporation à travers des membranes semicristallines en alcool polyvinylique. Il résulte de cette étude que l'état de l'eau une fois absorbée par un polymère hydrophile détermine le comportement de ce dernier lorsqu'il est utilisé sous forme de membrane pour traiter, par pervaporation, un mélange hydro-organique à miscibilité limitée. Nous avons souligné le rôle primordial de la cristallinité des membranes en alcool polyvinylique sur leur perméabilité en pervaporation vis-à-vis de l’eau, ainsi que des alcools étudiés (éthanol, 1-butanol et 1-octanol). Les cristallites peuvent être assimilées à des centres de réticulation multichaîne ; elles réduisent la possibilité de gonflemen

Nanoparticules originales à base de carboxylates de fer (encapsulation du busulfan, de l'AZT-TP et du cidofovir)

Cette thèse a comme but de préparer de nanoparticules de (MOF) ou plus précisément de carboxylates de fer présentant des taille compatibles avec une administration intraveineuse, porosités importante, une bonne biocompatibilité et des capacités d encapsulation et de libération de principes actifs d intérêt comme le busulfan (agent anticancéreux), l AZT-TP et le cidofovir (agents antirétroviraux). Dans la perspective des applications biomédicales, nous avons choisi la famille des carboxylates de fer pour préparer nos nanoparticules, car ces matériaux peuvent être élaborés à partir de fer et des acides di(ou tri) carboxyliques de très faible DL50.This thesis is intended to prepare nanoparticles (MOF) or more precisely iron carboxylates having a size compatible with intravenous, high porosity, good biocompatibility and capability of encapsulation and release of active ingredients of interest as busulfan (anticancer agent), AZT-TP and cidofovir (antiretrovirals). From the perspective of biomedical applications, we chose the family of iron carboxylates to prepare our nanoparticles, because these materials can be made from iron and acid di (or tri) carboxylic very low LD50.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Toward an optimized treatment of intracellular bacterial infections: input of nanoparticulate drug delivery systems

International audienceIntracellular pathogenic bacteria can lead to some of the most life-threatening infections. By evolving a number of ingenious mechanisms, these bacteria have the ability to invade, colonize and survive in the host cells in active or latent forms over prolonged period of time. A variety of nanoparticulate systems have been developed to optimize the delivery of antibiotics. Main advantages of nanoparticulate systems as compared with free drugs are an efficient drug encapsulation, protection from inactivation, targeting infection sites and the possibility to deliver drugs by overcoming cellular barriers. Nevertheless, despite the great progresses in treating intracellular infections using nanoparticulate carriers, some challenges still remain, such as targeting cellular subcompartments with bacteria and delivering synergistic drug combinations. Engineered nanoparticles should allow controlling drug release both inside cells and within the extracellular space before reaching the target cells