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The understanding of complement activation by nanomaterials is a key to a rational design of safe and efficient nanomedicines. This work proposed a systematic study investigating how molecular design of nanoparticle coronas made of dextran impacts on mechanisms that trigger complement activation. The nanoparticles used for this work consisted of dextran-coated poly(isobutylcyanoacrylate) (PIBCA) nanoparticles have already been thoroughly characterized. Their different capacity to trigger complement activation established on the cleavage of the protein C3 was also already described making these nanoparticles good models to investigate the relation between the molecular feature of their corona and the mechanism by which they triggered complement activation. Results of this new study show that complement activation pathways can be selected by distinct architectures formed by dextran chains composing the nanoparticle corona. Assumptions that explain the relation between complement activation mechanisms triggered by the nanoparticles and the nanoparticle corona molecular feature were proposed. These results are of interest to better understand how the design of dextran-coated nanomaterials will impact interactions with the complement system. It can open perspectives with regard to the selection of a preferential complement activation pathway or prevent the nanoparticles to activate the complement system, based on a rational choice of the corona configuration. [ABSTRACT FROM AUTHOR]

Abstract: The potential of siRNA to knock down expression of genes has been identified as an exciting strategy for specific treatments of disease-associated genes. However, their clinical development is pended to the achievement of their effective intracellular delivery in the target cells in vivo. So far, this was a bottleneck for fast development of siRNA in clinics because of their high enzymatic susceptibility in biological media and their poor intracellular uptake. The realization of therapeutic potential of the RNA interference approach strongly depended on the rational design of safe and effective carriers. This review considers carriers made of chitosan-based nanoparticles. It reports the methods of synthesis and the interactions of siRNA with chitosan which is at the basis of the association, stability and delivery to cells of siRNA with these carriers. Results of evaluations of the interference activity produced in vitro and in vivo by the interfering molecule delivered with chitosan-based nanoparticle carriers are discussed. As pointed out from different examples, the remarkable efficacy of the chitosan-based nanoparticles to deliver active interfering agents in vivo and to achieve a successful systemic delivery including by oral administration are very encouraging. Although we are still in the early stage of developments, it can be expected that results reported so far paved the road to stimulate further developments and strengthen their clinical application perspectives. [Copyright &y& Elsevier]

The scale-up of nanoemulsions (NEs) produced by emulsification and solvent diffusion process was successfully achieved in the present work. Up to 1500 mL of NEs were produced with olive oil, castor oil, almond oil, or Arlamol™ E by using a Y-shaped mixer device. NE droplet sizes were significantly modulated from 290 to 185 nm by changing the process parameters without modification of the formulation composition. Smaller NE droplet sizes were obtained by (1) decreasing the internal diameter of the Y-mixer from 5 to 0.8 mm, (2) increasing the flow rates of the organic and the aqueous phases upon mixing, and (3) increasing the temperature of the experiment from 5°C to 40°C. All the results of NE diameters ( dsc) expressed as a function of the Reynolds number ( Re) and the shear rate inside the Y-mixer ( \documentclass{article}\usepackage{amssymb}\begin{document}\pagestyle{empty}$\dot \gamma$\end{document}) showed the existence of typical power-law relationships: dsc = 102.82 Re− 0.14 and \documentclass{article}\usepackage{amssymb}\begin{document}\pagestyle{empty}$d_{{\rm sc}} = 10^{2.60} \dot \gamma ^{- 0.06}$\end{document}, respectively. The existence of these power-laws for NE formation by emulsification and solvent diffusion process has never been reported in the literature yet and constitutes a new finding in this work. We definitely proved that the high turbulences created upon NE formation are the most important parameter allowing to decrease droplet size. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4240-4247, 2012 [ABSTRACT FROM AUTHOR]

Abstract: Four types of nanoparticles with core-diffuse shell structures have been synthesized through self-assembly of PICBA-Dextran block copolymers. These nanoparticles are designed to carry pharmaceutically active molecules into the human body through injection into the blood stream. In this work, we have determined how the characteristics of the diffuse shell influence the adsorption of three types of proteins: Bovine Serum Albumin (BSA), fibrinogen, and a protein from the complement system that triggers recognition and elimination by macrophages. We have determined the structural characteristics of the diffuse shells using Nuclear Magnetic Resonance (NMR), Small Angle Neutron Scattering (SANS) and Quasi-Elastic Light Scattering (QELS). We have measured the adsorption of Bovine Serum Albumin (BSA) through Immunodiffusion methods, and found that it adsorbed in substantial amounts even when the distance between dextran chains at the core-diffuse shell interface is quite short. We have observed the aggregation of the nanoparticles induced by fibrinogen, and found that it was prevented when the density of dextran chains protruding from the core surface was sufficiently high. Finally we have measured the activation of the complement system by the nanoparticles, and found that it was also limited by the surface density of dextran chains that protrude from the core and by their mesh size within the diffuse shell. [Copyright &y& Elsevier]

Abstract: The study is focused on the evaluation of the potential bioadhesive behaviour of chitosan and thiolated chitosan (chitosan-TBA)-coated poly(isobutyl cyanoacrylates) (PIBCA) nanoparticles. Nanoparticles were obtained by radical emulsion polymerisation with chitosan of different molecular weight and with different proportions of chitosan/chitosan-TBA. Mucoadhesion was ex vivo evaluated under static conditions by applying nanoparticle suspensions on rat intestinal mucosal surfaces and evaluating the amount of nanoparticles remaining attached to the mucosa after incubation. The analysis of the results obtained demonstrated that the presence of either chitosan or thiolated chitosan on the PIBCA nanoparticle surface clearly enhanced the mucoadhesion behaviour thanks to non-covalent interactions (ionic interaction and hydrogen bonds) with mucus chains. Both, the molecular weight of chitosan and the proportion of chitosan-TBA in the formulation influenced the nanoparticle hydrodynamic diameter and hence their transport through the mucus layer. Improved interpenetration ability with the mucus chain during the attachment process was suggested for the chitosan of high molecular weight, enhancing the bioadhesiveness of the system. The presence of thiol groups on the nanoparticle surface at high concentration (200×10−6 μmolSH/cm2) increased the mucoadhesion capacity of nanoparticles by forming covalent bonds with the cysteine residues of the mucus glycoproteins. [Copyright &y& Elsevier]

Abstract: The aim of this work was to examine the in vitro interactions of core-shell poly(isobutylcyanoacrylate)-polysaccharide nanoparticles (NP) with blood proteins. The particles were prepared by initiating the emulsion polymerization of isobutylcyanoacrylate (IBCA) in the presence of dextran 71 or 15kDa, heparin, a blend of dextran 71 and heparin, or dextran sulphate in aqueous medium at pH 1. The mechanisms of polymerisation were redox radical (Rad) or anionic (An), resulting in differences in the spatial arrangement of the polysaccharide chains at the NP surface, i.e. “loops” and “trains” by anionic polymerization, “brush” by radical polymerization. Surface composition of NPs was determined by X-ray photo-electron spectroscopy (XPS) and surface charge by zeta potential measurements. In the presence of citrated blood plasma, efficacy of the steric repulsive effect of the NP dextran shell towards protein adsorption decreased in the order: Dex71-Rad>Dex15-Rad>Dex71-An⪢Dex15-An. Dextran-coated NPs adsorbed ApoA-I and fibrinogen from plasma. Concerning activation of complement in serum, the effect was sharp: Dex71-Rad was a very low activator whereas Dex15-An, Dex15-Rad and Dex71-An were strong activators. In citrated plasma, the steric repulsive effects of Hep-Rad and Dex-Hep-Rad NPs were similar to Dex71-An, and Dex-Sulph-Rad NPs adsorbed twice more proteins than Hep-Rad. Hep-Rad, Dex-Hep-Rad and Dex-Sulph-Rad NPs adsorbed IgG and fibrinogen. Complement was not activated in serum in the presence of Hep-Rad and Dex-Hep-Rad and a slight adsorption of C3 was noted. C3 was completely adsorbed on Dex-Sulph-Rad. The exquisite sensitivity of blood proteins to differences in the nature and outermost structure of the polysaccharides-coated NPs is highlighted by the present results. [Copyright &y& Elsevier]

The aim of the work was to evaluate in vitro and in vivo the effect of the addition of poly(ethylene glycol) ( PEG) to paclitaxel ( PTX)-cyclodextrin poly(anhydride) nanoparticles. For this, PTX in poly(anhydride) nanoparticles complexed with cyclodextrins (either 2-hydroxypropyl-β-cyclodextrin or β-cyclodextrin) and combined with PEG 2000 were prepared by the solvent displacement method. Intestinal permeability in vitro and in vivo pharmacokinetic studies in C57BL/6J mice were performed. Nanoparticle formulations containing PTX increased its apparent permeability through rat intestine in vitro in the Ussing chambers, enhancing its permeability 10-15 times compared with commercial Taxol®. In addition, in pharmacokinetic studies, drug plasma levels were observed for at least 24 h leading to a relative oral bioavailability between 60% and 80% for PTX complexed with cyclodextrin and loaded in pegylated poly(anhydride) nanoparticles after oral gavage. In all, PTX-cyclodextrin complexes encapsulated in pegylated nanoparticles managed to promote the intestinal uptake of the drug displaying sustained plasma levels after oral administration to laboratory animals with a more prolonged plasma profile compared with the formulation with no PEG at all. Therefore, pegylated poly(anhydride) nanoparticles represent a promising carrier for the oral delivery of PTX. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:2877-2886, 2015 [ABSTRACT FROM AUTHOR]

Highlights: [•] Scale-up of polyamide and polyester nanocapsules loaded with Parsol® MCX. [•] Interfacial polycondensation and solvent diffusion method. [•] Modulation of nanocapsule sizes by changing the process parameters. [•] Power–law relationship between nanocapsule size and the Reynolds number. [ABSTRACT FROM AUTHOR]

Abstract: Chitosan-thiobutylamidine was developed and evaluated as a novel tool for gene delivery. The conjugate, displaying 299.1±11.5μmol free thiol groups per gram polymer, formed coacervates with pDNA at a mean size of 125nm and a zeta potential of +9mV. Thiol groups, being susceptible for oxidation, were immobilised on the polymeric backbone of chitosan in order to introduce the property of extracellular stability and intracellular pDNA release by forming reversible disulfide bonds. The integrity of the new particles was compared to unmodified chitosan under simulated physiological conditions. Within 10h, pDNA was completely released from chitosan–DNA particles while only 12% were released from the thiomer-based particles. At pH 7, the amount of thiol groups significantly (p<0.05) decreased by more than 25% within 6h. In contrast, in a reducing environment as found intracellularly, chitosan-thiobutylamidine–DNA nanoparticles dissociated continuously, liberating approximately 50% of pDNA within 3h. Transfection studies performed in a Caco2 cell culture evinced the highest efficiency for chitosan-thiobutylamidine–DNA nanoparticles in combination with a glycerol shock solution. The combination of improved stability, enhanced pDNA release under reducing conditions, and higher transfection efficiency identifies chitosan-thiobutylamidine as a promising new vector for gene delivery. [Copyright &y& Elsevier]

A new generation of drug delivery systems based on heparin–poly(isobutylcyanoacrylate) copolymers has been developed to carry hemoglobin. These copolymers spontaneously form, in water, nanoparticles with a ciliated surface of heparin. These nanoparticles maintain the heparin antithrombic properties and inhibit complement activation. One ml of nanoparticle suspension can be loaded with up to 2.1 mg of hemoglobin, which preserves its ligand binding capacity. This work constitutes the first demonstration of hemoglobin loaded on nanoparticle surface, rather than being encapsulated. With a size of 100 nm, these drug delivery systems make suitable tools in the treatment of thrombosis oxygen deprived pathologies. [Copyright &y& Elsevier]

Oil-in-water nanoemulsions were prepared using a series of synthetic graft copolymers with a backbone of dextran (DEX) and a number of side chains of poly-&epsiv;-caprolactone (PCL). In this paper, we focus on the o/w emulsion stabilizing abilities of these novel PCL-DEX copolymers, using a recently developed optical analyzer (Turbiscan). The main advantage of Turbiscan is to detect the destabilization phenomena in non-diluted emulsion, much earlier than the naked eye’s operator, especially in the case of an opaque and concentrated system. This study shows that PCL-DEX copolymers successfully stabilized ethyl acetate-in-water emulsions, even in the absence of additional surfactants, whereas they were not efficient in stabilizing methylene chloride-in-water emulsions which coalesced fast and irreversibly. The ethyl acetate-in-water emulsion stabilizing ability of PCL-DEX seemed to be related to the localization of their blocks with regard to the oil–water interface. [Copyright &y& Elsevier]

The aim of the present work was to evaluate the mucoadhesive properties of poly(isobutyl cyanoacrylate) (PIBCA) nanoparticles (NPs) coated with Low Molecular Weight (LMW) chitosan (CS)- and glycol chitosan (GCS)-based thiomers as well as with the corresponding LMW unmodified polysaccharides. For this purpose, all the CS- and GCS-based thiomers were prepared under simple and mild conditions starting from the LMW unmodified polymers CS and GCS. The resulting NPs were of spherical shape with diameters ranging from 400 to 600 nm and 187 to 309 nm, for CS- and GCS-based NPs, respectively. The mucoadhesive characteristics of these core shell NPs were studied in Ussing chambers measuring the percentage of NPs stuck on the mucosal of fresh intestinal tissue after 2 h of incubation. Moreover, incubation of nanoparticle formulations with the intestinal tissue induced changes in transmucosal electrical resistance which were measured to gain information into the opening of tight junctions and to control the integrity of the mucosa. Thus, it was found that PIBCA NPs coated with the GCS–Glutathione conjugate (GCGPIBCA NPs) possessed the most favorable mucoadhesive performances. Moreover, both GCGPIBCA- and GCS- N -acetyl-cysteine (GCNPIBCA)-core-shell NPs might induced an enlargement of the epithelial cell tight junctions. In conclusion, coating of PIBCA NPs with GCS-based thiomers may be useful for improving the mucoadhesive and permeation properties of these nanocarriers. [ABSTRACT FROM AUTHOR]

Abstract: PLGA-PEG nanocapsules containing a liquid core of perfluorooctyl bromide were synthesized by an emulsion-evaporation process and designed as contrast agents for 19F MRI. Physico-chemical properties of plain and PEGylated nanocapsules were compared. The encapsulation efficiency of PFOB, estimated by 19F NMR spectroscopy, is enhanced when using PLGA-PEG instead of PLGA. PLGA-PEG nanocapsule diameter, measured by Dynamic Light Scattering is around 120 nm, in agreement with Transmission Electron microscopy (TEM) observations. TEM and Scanning Electron Microscopy (SEM) reveal that spherical core–shell morphology is preserved. PEGylation is further confirmed by Zeta potential measurements and X-ray Photoelectron Spectroscopy. In vitro, stealthiness of the PEGylated nanocapsules is evidenced by weak complement activation. Accumulation kinetics in the liver and the spleen was performed by 19F MRI in mice, during the first 90 min after intravenous injection. In the liver, plain nanocapsules accumulate faster than their PEGylated counterparts. We observe PEGylated nanocapsule accumulation in CT26 xenograft tumor 7 h after administration to mice, whereas plain nanocapsules remain undetectable, using 19F MRI. Our results validate the use of diblock copolymers for PEGylation to increase the residence time of nanocapsules in the blood stream and to reach tumors by the Enhanced Permeation and Retention (EPR) effect. [Copyright &y& Elsevier]

Abstract: Biomimetic nanoparticles based on polysaccharides–poly(alkylcyanoacrylates) copolymers were initially developed in view of drug delivery. Core-shell nanoparticles covered with a sufficiently long brush of polysaccharides were shown to be very low complement activators and have the potential for long circulation times in the bloodstream. Such nanoparticles bearing haemoglobin were envisaged as potential red cell substitutes. Different core-shell nanoparticles with a brush shell made of dextran, dextran-sulphate, or heparin were prepared and haemoglobin (Hb) could be adsorbed on their surface. Benzene tetracarboxylic acid (BTCA) was used as a coupling agent for Hb to dextran-coated nanoparticles; the Hb loading capacity of the dextran nanoparticles showed a 9.3 fold increased. The coupled Hb maintained the allosteric properties of free Hb. While modification of nanoparticles by BTCA slightly increased complement activation, the further addition of Hb totally reversed this effect providing Hb-loaded nanoparticles with a very low level of complement activation. Such nanoparticles could be a suitable alternative to haemoglobin solutions in the development of a blood substitute. [Copyright &y& Elsevier]

Abstract: The surface of polymeric nanocapsules used as ultrasound contrast agents (UCAs) was modified with PEGylated phospholipids in order to escape recognition and clearance by the mononuclear phagocyte system and achieve passive tumor targeting. Nanocapsules consisted of a shell of poly(lactide-co-glycolide) (PLGA) encapsulating a liquid core of perfluorooctyl bromide (PFOB). They were decorated with poly(ethylene glycol-2000)-grafted distearoylphosphatidylethanolamine (DSPE-PEG) incorporated in the organic phase before the solvent emulsification–evaporation process. The influence of DSPE-PEG concentration on nanocapsule size, surface charge, morphology, hydrophobicity and complement activation was evaluated. Zeta potential measurements, Hydrophobic interaction chromatography and complement activation provide evidence of DSPE-PEG presence at nanocapsule surface. Electronic microscopy reveals that the core/shell structure is preserved up to 2.64 mg of DSPE-PEG for 100 mg PLGA. In vivo ultrasound imaging was performed in mice bearing xenograft tumor with MIA PaCa-2 cells, either after an intra-tumoral or intravenous injection of nanocapsules. Tumor was observed only after the intra-tumoral injection. Despite the absence of echogenic signal in the tumor after intravenous injection of nanocapsules, histological analysis reveals their accumulation within the tumor tissue demonstrating that tissue distribution is not the unique property required for ultrasound contrast agents to be efficient. [Copyright &y& Elsevier]

Abstract: In this study, microspheres designed for embolization, defined as GF2000-Trisacryl® MS (GF-MS) and DEAE-Trisacryl® MS (DEAE-MS), were originally PEGylated using (3-amino propyl) triethoxy silane as coupling agent. Indomethacin was loaded into both PEGylated and non-PEGylated DEAE-MS, displaying ion-exchange ability, through a batch process with a respective capacity of 1.2 and 0.25g/g. The morphology of naked and PEGylated MS was evaluated by scanning electron microscopy (SEM). Both micosphere resins surface looked like orange skin, although DEAE-MS showed a slightly rougher surface due to the copolymerization process. PEGylated microspheres have a most likely swelling surface owing to the presence of PEG hydrophilic chains. The mean diameters were of about 66 and 60μm for GF-MS and DEAE-MS, respectively. Data obtained for PEGylated MS by Fourier Transform Infrared spectroscopy (FTIR) confirmed that microspheres were successfully PEGylated. Finally, complement activation in vitro was performed to evaluate the activating capacity of different microspheres. Both PEGylated GF-MS and DEAE-MS activated the complement system of about 33% less than their corresponding naked microspheres, while loading PEGylated DEAE-MS with indomethacin almost suppressed complement activation. This inhibiting role implies that PEGylation as well as loading the microspheres with anti-inflammatory drug has a compact effect on the interaction of microspheres with blood proteins. [Copyright &y& Elsevier]

[Display omitted] • Understands nanoparticle oral drug delivery potential from their characteristics. • Identifies nanoparticle characteristics on interaction mechanisms with gut mucosa. • Nanoparticles-gut interactions are molecularly driven complex mechanisms. • Should Interest formulators to address oral drug delivery challenges using nanoparticles. A better knowledge on influence of nanomedicine characteristics on their biological efficacy and safety is expected to accelerate their clinical translation. This work aimed understanding of the oral fate of polymer-based nanomedicines designed with different characteristics. The influence of nanoparticle characteristics (size, zeta potential, molecular architecture surface design) was explored on biological responses evaluating their retention and absorption by rat jejunum using the Ussing chamber experimental model. Thermodynamic aspects of interactions between nanoparticles and model mucins were elucidated by isothermal titration calorimetry. The retention on mucosa varied between nanoparticles from 18.5 to 97.3 % of the initial amount after a simulation considering the entire jejunum length. Different mechanisms were proposed which promoted mucosal association or oppositely precluded any interactions. Strikingly, mucosal retention was profoundly affected by the size and nature of interactions with the mucus which depended on the nature of the coating material, but not on the zeta potential. The nanoparticle absorption simulated along the whole length of the intestine was low (0.01 to almost 3% of the initial amounts). A saturable mechanism including an upper nanoparticle size limit was evidenced but, needs now to be further elucidated. This work showed that the molecular design and formulation of nanoparticles can guide mechanisms by which nanoparticles interact with the mucosa. The data could be useful to formulators to address different oral drug delivery challenges ranging from the simple increase of residence time and proximity to the absorptive epithelium and systemic delivery using the most absorbed nanoparticles. [ABSTRACT FROM AUTHOR]