Nanoparticles facing the gut barrier: Retention or mucosal absorption? Mechanisms and dependency to nanoparticle characteristics.

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.

Understanding Nanomedicine Size and Biological Response Dependency: What Is the Relevance of Previous Relationships Established on Only Batch-Mode DLS-Measured Sizes?

PURPOSE: Most relationships between size and nanomedicine performance and safety were established before the early 2010s' when batch-mode dynamic light scattering (batch-mode DLS) was the only easy size measurement method for colloids available. They are basis for the rational design of nanomedicines, but misunderstood contrasting results are reported. This work aimed to investigate whether these relationships can be used with confidence knowing that batch-mode DLS can be tricky when measuring sizes of polydisperse systems. METHODS: A polydisperse dispersion of polymer nanoparticles ranging from 100 to 465 nm was synthesized. The particles were separated in 4 fractions by successive centrifugations. The capacity of each fraction and parent dispersion to activate the complement system was evaluated by Crossed immuno-electrophoresis. RESULTS: Each fraction was a population of particles with a distinct size. It showed a different capacity to activate the complement system. Particles of the fractions showing the strongest capacity to activate the complement systems had a different size evaluated by batch-mode DLS then that of the parent particles. CONCLUSION: Particles activating the complement system in the parent dispersion were not those that were detected by batch-mode DLS while measuring its size. This work pointed out that previously established relationships between nanomedicine size and their biological response should be taken with caution if sizes were only measured by batch-mode DLS.

Counterion of Chitosan Influences Thermodynamics of Association of siRNA with a Chitosan-Based siRNA Carrier.

PURPOSE: The work aimed to compare quality of a siRNA carrier prepared with chitosan of two different sources having similar degree of deacetylation and molecular weights. Differences were analyzed from thermodynamic characteristics of interactions with siRNA. METHODS: The siRNA carrier (chitosan-coated poly(isobutylcyanoacrylate) nanoparticles) was prepared with home-prepared, CSLab, and commercial, CSCom, chitosans. Chitosan counterion was identified and chitosans CSCommod1 and CSCommod2 were obtained from CSCom exchanging counterion with that found on CSLab. Carrier quality was checked considering the size, zeta potential and siRNA association capacity by gel electrophoresis. Thermodynamic parameters of interactions between siRNA and chitosans in solution or immobilized at the carrier surface were determined by isothermal titration calorimetry (ITC). RESULTS: CSLab and CSCommod2 having a high content of acetate counterion associated better siRNA than CSCom and CSCommod1 which counterion included mainly chloride. ITC measurements indicated that siRNA interactions with chitosan and the siRNA carrier were driven by entropic phenomena including dehydration, but thermodynamic parameters of interactions clearly differed according to the nature of the counterion of chitosan. The influence of chitosan counterions was interpreted considering their different lyotropic character. CONCLUSION: Association of siRNA with our siRNA carrier was influenced by the nature of counterions associated with chitosan. Driven by entropic phenomena including dehydration, interactions were favored by acetate counterion. Although more work would be needed to decipher the influence of the counterion of chitosan during association with siRNA, it was pointed out as a new critical attribute of chitosan to consider while formulating siRNA carrier with this polysaccharide.

Preparation of a Carrier to Achieve In Vivo Delivery of siRNA: The Example of Chitosan-Coated Poly(isobutylcyanoacrylate) Nanoparticles.

This chapter describes the preparation of chitosan-coated poly(isobutylcyanoacrylate) nanoparticles as a suitable carrier to deliver siRNAs to two types of xenograft tumor models of mice. The nanoparticles are prepared by a method of emulsion polymerization that includes steps of polymerization and purification. The polymerization method is carried out in a single pot in an aqueous medium. siRNAs are coupled with the nanoparticles at the end of the preparation by adsorption. The protocol also explains how to determine optimum yield/the titer of association of siRNA with the nanoparticles. It is described for a preparation scale at 4 mL of nanoparticle dispersion at a concentration of 42-46 mg nanoparticles/mL. Optimal loading capacity of the nanoparticles with the siRNA can be achieved by performing an association yield above 90% using a mass ratio of 1 mg siRNA/50 mg of nanoparticles (20 µg siRNA/mg nanoparticles, 1 nmol siRNA (Mw 14 kDa)/mg nanoparticles).

A journey through the emergence of nanomedicines with poly(alkylcyanoacrylate) based nanoparticles.

Starting in the late 1970s, the pioneering work of Patrick Couvreur gave birth to the first biodegradable nanoparticles composed of a biodegradable synthetic polymer. These nanoparticles, made of poly(alkylcyanoacrylate) (PACA), were the first synthetic polymer-based nanoparticulate drug carriers undergoing a phase III clinical trial so far. Analyzing the journey from the birth of PACA nanoparticles to their clinical evaluation, this paper highlights their remarkable adaptability to bypass various drug delivery challenges found on the way. At present, PACA nanoparticles include a wide range of nanoparticles that can associate drugs of different chemical nature and can be administered in vivo by different routes. The most recent technologies giving the nanoparticles customised functions could also be implemented on this family of nanoparticles. Through different examples, this paper discusses the seminal role of the PACA nanoparticles' family in the development of nanomedicines.

Assessment of Complement Activation by Nanoparticles: Development of a SPR Based Method and Comparison with Current High Throughput Methods.

PURPOSE: A Surface Plasmon Resonance chip (SPR) was developed to study the activation of complement system triggered by nanomaterials in contact with human serum, which is an important concern today to warrant safety of nanomedicines. METHODS: The developed chip was tested for its specificity in complex medium and its longevity of use. It was then employed to assess the release of complement fragments upon incubation of nanoparticles in serum. A comparison was made with other current methods assessing complement activation (µC-IE, ELISA). RESULTS: The SPR chip was found to give a consistent response for C3a release upon activation by nanoparticles. Results were similar to those obtained by µC-IE. However, ELISA detection of iC3b fragments showed an explained high non-specific background. The impact of sample preparation preceding the analysis was assessed with the newly develop SPR method. The removal of nanoparticles before analysis showed an important modification in the obtained response, possibly leading to false negative results. CONCLUSION: The SPR chip developed in this work allows for an automated assessment of complement activation triggered by nanoparticles with possibility of multiplexed analysis. The design of the chip proved to give consistent results of complement activation by nanoparticles.

Characterization of nanomedicines: A reflection on a field under construction needed for clinical translation success.

The nanotechnology revolution offers many expectations for the improvement of medicine treatments. At present, nanomedicine (NM) development is hampered by methodological barriers for a better characterization and a wider understanding of their in vivo behavior. While regulatory agencies setup guidelines to support NM translation from bench to bedside, the gap is still hardly overcome by main nanomedicines. One lever for filling this gap is a better characterization, thus increasing the global knowledge about the NM itself but also validate the confidence in terms of batch to batch reproducibility of such complex nano-objects. Here, we review the current methodologies routinely used for clinical release of nanomedicine batches in compliance with official guidelines. We confront them to the extreme sharpness of biological systems and finally discuss future possible orientations for a better characterization of NMs, needed to bridge the gap between physicochemical properties and biological fate.

Development of a Gas Chromatography Method for the Analysis of Copaiba Oil.

A rapid, simple, precise and economic method for the quantification of main compounds of copaiba resin and essential oils (Copaifera langsdorffii Desf.) by gas chromatography (GC) has been developed and validated. Copaiba essential oil was extracted by hydrodistillation from the copaiba resin. Resin derivatization allowed the identification of diterpenes compounds. A gas chromatography-mass spectroscopy (GC/MS) method was developed to identify compounds composing the copaiba resin and essential oil. Then the GC/MS method was transposed to be used with a flame ionization detector (FID) and validated as a quantitative method. A good correlation between GC/MS and GC/FID was obtained favoring method transposition. The method showed satisfactory sensitivity, specificity, linearity, precision, accuracy, limit of detection and limit of quantitation for ß-caryophyllene, α-humulene and caryophyllene oxide analyses in copaiba resin and essential oils. The main compounds identified in copaiba essential oil were ß-bisabolene (23.6%), ß-caryophyllene (21.7%) and α-bergamotene (20.5%). Copalic acid methyl ester (15.6%), ß-bisabolene (12.3%), ß-caryophyllene (7.9%), α-bergamotene (7.1%) and labd-8(20)-ene-15,18-dioic acid methyl ester (6.7%) were diterpenes identified from the derivatized copaiba resin. The proposed method is suitable for a reliable separation, identification and quantification of compounds present in copaiba resin and essential oil. It could be proposed as an analytical method for the analysis of copaiba oil fraction in raw and essential oil parent extracts and after they have been incorporate in pharmaceutical formulations.

Mucoadhesive properties of low molecular weight chitosan- or glycol chitosan- and corresponding thiomer-coated poly(isobutylcyanoacrylate) core-shell nanoparticles.

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 600nm and 187 to 309nm, 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 2h 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.

Tuning complement activation and pathway through controlled molecular architecture of dextran chains in nanoparticle corona.

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.

Match of Solubility Parameters Between Oil and Surfactants as a Rational Approach for the Formulation of Microemulsion with a High Dispersed Volume of Copaiba Oil and Low Surfactant Content.

PURPOSE: Aim was to formulate oil-in-water (O/W) microemulsion with a high volume ratio of complex natural oil, i.e. copaiba oil and low surfactant content. The strategy of formulation was based on (i) the selection of surfactants based on predictive calculations of chemical compatibility between their hydrophobic moiety and oil components and (ii) matching the HLB of the surfactants with the required HLB of the oil. METHOD: Solubility parameters of the hydrophobic moiety of the surfactants and of the main components found in the oil were calculated and compared. In turn, required HLB of oils were calculated. Selection of surfactants was achieved matching their solubility parameters with those of oil components. Blends of surfactants were prepared with HLB matching the required HLB of the oils. Oil:water mixtures (15:85 and 25:75) were the titrated with surfactant blends until a microemulsion was formed. RESULTS: Two surfactant blends were identified from the predictive calculation approach. Microemulsions containing up to 19.6% and 13.7% of selected surfactant blends were obtained. CONCLUSION: O/W microemulsions with a high volume fraction of complex natural oil and a reasonable surfactant concentration were formulated. These microemulsions can be proposed as delivery systems for the oral administration of poorly soluble drugs.

Serial multiple crossed immunoelectrophoresis at a microscale: A stamp-sized 2D immunoanalysis of protein C3 activation caused by nanoparticles.

Crossed immunoelectrophoresis (C-IE) is used to detect and quantify specific proteins. An application allowed the evaluation of complement system activation by nanomaterials. The work aimed to improve the C-IE toward a higher throughput and less tedious method. A new concept was implemented to prepare and run agarose gels. The first and the second dimension of electrophoresis were performed on a single gel plate, prepared before the beginning of the analysis. Several samples were migrated simultaneously on the same migration line. Up to 35 analyses were run at once, providing stamp-sized electrophoregrams (2.8 × 3 cm(2) ) maintaining the performance of the original method performed on 5 × 7 cm(2) gel slabs. Robustness and precision of the method were demonstrated through a validation approach using ANOVA. Handling, experimental duration, amount of reagents, and overall cost of one analysis were considerably reduced compared to the original method. With the same equipment, seven times more analyses can be performed in one run. C-IE can be used to analyze many types of proteins. The new experimental modalities were suitable for the application developed in the present work that was to evaluate activation of protein C3 of the complement system triggered by nanomaterials.

Multimodal Dispersion of Nanoparticles: A Comprehensive Evaluation of Size Distribution with 9 Size Measurement Methods.

PURPOSE: Evaluation of particle size distribution (PSD) of multimodal dispersion of nanoparticles is a difficult task due to inherent limitations of size measurement methods. The present work reports the evaluation of PSD of a dispersion of poly(isobutylcyanoacrylate) nanoparticles decorated with dextran known as multimodal and developed as nanomedecine. METHODS: The nine methods used were classified as batch particle i.e. Static Light Scattering (SLS) and Dynamic Light Scattering (DLS), single particle i.e. Electron Microscopy (EM), Atomic Force Microscopy (AFM), Tunable Resistive Pulse Sensing (TRPS) and Nanoparticle Tracking Analysis (NTA) and separative particle i.e. Asymmetrical Flow Field-Flow Fractionation coupled with DLS (AsFlFFF) size measurement methods. RESULTS: The multimodal dispersion was identified using AFM, TRPS and NTA and results were consistent with those provided with the method based on a separation step prior to on-line size measurements. None of the light scattering batch methods could reveal the complexity of the PSD of the dispersion. CONCLUSIONS: Difference between PSD obtained from all size measurement methods tested suggested that study of the PSD of multimodal dispersion required to analyze samples by at least one of the single size particle measurement method or a method that uses a separation step prior PSD measurement.

Gelation and micellization behaviors of pluronic(®) F127 hydrogel containing poly(isobutylcyanoacrylate) nanoparticles specifically designed for mucosal application.

The aim of this investigation is to combine the advantages of pluronic(®) F127 hydrogels and nanoparticles composed of poly(isobutylcyanoacrylate) (PIBCA) core coated with a mixture of chitosan and thiolated chitosan to design novel multifunctional formulation for mucosal application. Nanoparticles offer the advantage of being mucoadhesive while pluronic(®) F127 hydrogel allowed prolonged contact time onto mucosal surfaces. This work highlights an unprecedented comprehensive study on the effect of nanoparticles on gelation and micellization behaviors of pluronic(®) F127 using rheology and micro-calorimetry experiments. Results showed that presence of nanoparticles induced (i) smaller crystal peak of F127, (ii) a decrease of the enthalpy of F127 micellization and (iii) a non-reversibility of micelle formation (during heating ramp) and micelle melting (during cooling ramp). Together, these findings suggest that a part of F127 was not able to associate into micelles and the formation of mixed micelles containing F127 unimers and PIBCA/(chitosan/thiolated chitosan) copolymer and/or PIBCA homopolymer was suspected. The interaction of F127 unimers with nanoparticles resulted from their physical de-structuration as revealed by nanoparticle size measurement. In addition, we found that short polymerization duration of one hour induced more pronounced nanoparticle de-structuration. Twenty-four hour-polymerization of isobutylcyanoacrylate in the presence of chitosan and thiolated chitosan led to more stable nanoparticles when mixed with pluronic(®) F127.

Cell line-dependent cytotoxicity of poly(isobutylcyanoacrylate) nanoparticles coated with chitosan and thiolated chitosan: Insights from cultured human epithelial HeLa, Caco2/TC7 and HT-29/MTX cells.

Nanoparticles composed of poly(isobutylcyanoacrylate) core coated with a mixture of chitosan and thiolated chitosan have already shown promising results in terms of mucoadhesion and permeation enhancement properties of pharmaceutical active drugs delivered via mucosal routes. In the present work, the cytotoxicity of these nanoparticles was first investigated using direct contact assay on undifferentiated human cervix epithelial HeLa cells. The results showed strong toxicity in HeLa cells for the two investigated concentrations 25 and 50 µg/mL. The cytotoxic effect was mainly attributed to the poly(isobutylcyanoacrylate) core since no significant differences in nanoparticle cytotoxicity were reported when nanoparticle shell composition was modified by adding chitosan or thiolated chitosan. In contrast, lower nanoparticle toxicity was reported using human fully-differentiated enterocyte-like Caco-2/TC7, and fully-differentiated mucus-secreting HT-29/MTX cells forming monolayer in culture mimicking an intestinal epithelial barrier. This study demonstrated that the toxicity of poly(isobutylcyanoacrylate) nanoparticles is highly cell line-dependent.

Protein-nanoparticle interactions evaluation by immunomethods: Surfactants can disturb quantitative determinations.

The adsorption of proteins on nanoparticle surface is one of the first events that occur when nanoparticles enter in the blood stream, which influences nanoparticles lifetime and further biodistribution. Albumin, which is the most abundant protein in serum and which has been deeply characterized, is an interesting model protein to investigate nanoparticle-protein interactions. Therefore, the interaction of nanoparticles with serum albumin has been widely studied. Immunomethods were suggested for the investigation of adsorption isotherms because of their ease to quantify the non-adsorbed bovine serum albumin without the need of applying separation methods that could modify the balance between the adsorbed and non-adsorbed proteins. The present work revealed that this method should be applied with caution. Artifacts in the determination of free protein can be generated by the presence of surfactants such as polysorbate 80, widely used in the pharmaceutical and biomedical field, that are needed to preserve the stability of nanoparticle dispersions. It was shown that the presence of traces of polysorbate 80 in the dispersion leads to an overestimation of the amount of bovine serum albumin remaining free in the dispersion medium when determined by both radial immunodiffusion and rocket immunoelectrophoresis. However, traces of poloxamer 188 did not result in clear perturbed migrations. These methods are not appropriate to perform adsorption isotherms of proteins on nanoparticle dispersions containing traces of remaining free surfactant. They should only be applied on dispersions that are free of surfactant that is not associated with nanoparticles.

Interactions of PLGA nanoparticles with blood components: protein adsorption, coagulation, activation of the complement system and hemolysis studies.

The intravenous administration of poly(lactic-co-glycolic) acid (PLGA) nanoparticles has been widely reported as a promising alternative for delivery of drugs to specific cells. However, studies on their interaction with diverse blood components using different techniques are still lacking. Therefore, in the present work, the interaction of PLGA nanoparticles with blood components was described using different complementary techniques. The influence of different encapsulated compounds/functionalizing agents on these interactions was also reported. It is worth noting that all these techniques can be simply performed, without the need for highly sophisticated apparatus or skills. Moreover, their transference to industries and application of quality control could be easily performed. Serum albumin was adsorbed onto all types of tested nanoparticles. The saturation concentration was dependent on the nanoparticle size. In contrast, fibrinogen aggregation was dependent on nanoparticle surface charge. The complement activation was also influenced by the nanoparticle functionalization; the presence of a functionalizing agent increased complement activation, while the addition of an encapsulated compound only caused a slight increase. None of the nanoparticles influenced the coagulation cascade at low concentrations. However, at high concentrations, cationized nanoparticles did activate the coagulation cascade. Interactions of nanoparticles with erythrocytes did not reveal any hemolysis. Interactions of PLGA nanoparticles with blood proteins depended both on the nanoparticle properties and the protein studied. Independent of their loading/surface functionalization, PLGA nanoparticles did not influence the coagulation cascade and did not induce hemolysis of erythrocytes; they could be defined as safe concerning induction of embolization and cell lysis.

Controlled Release, Intestinal Transport, and Oral Bioavailablity of Paclitaxel Can be Considerably Increased Using Suitably Tailored Pegylated Poly(Anhydride) Nanoparticles.

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-ß-cyclodextrin or ß-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.

Drug-free chitosan coated poly(isobutylcyanoacrylate) nanoparticles are active against trichomonas vaginalis and non-toxic towards pig vaginal mucosa.

PURPOSE: The present work reports a non-conventional therapeutic strategy based on the use of vaginally-applied formulations for the treatment of trichomoniasis due to Trichomonas vaginalis without adding a drug. METHODS: The formulations were based on a thermosensitive pluronic® F127 hydrogel containing mucoadhesive poly(isobutylcyanoacrylate) nanoparticles coated with a mixture of chitosan and thiolated chitosan (75/25 wt%). The nanoparticles were obtained by anionic emulsion polymerization of isobutylcyanoacrylate. The anti-T. vaginalis activity of the formulations was evaluated in vitro. RESULTS: Chitosan-coated nanoparticles showed a strong anti-T. vaginalis activity at 100 µg/mL independently on the proportion of thiolated chitosan. No anti-T. vaginalis activity was reported neither with chitosan-uncoated poly(isobutylcyanoacrylate) nanoparticles nor with chitosan used as a solution. These results suggest that the anti-T. vaginalis activity was related to poly(isobutylcyanoacrylate) nanoparticles but only when they are coated with chitosan. Histological analysis of ex vivo pig vaginal mucosa in contact with pluronic® F127 hydrogel containing poly(isobutylcyanoacrylate) nanoparticles coated with the mixture chitosan/thiolated chitosan (75/25 wt%) did not reveal any toxicity. CONCLUSION: This study demonstrated that poly(isobutylcyanoacrylate) nanoparticles coated with chitosan were active against T. vaginalis without adding a drug. Besides their anti-T. vaginalis activity, the formulations are non-toxic towards pig vaginal mucosa.

Peptide-functionalized nanoparticles for selective targeting of pancreatic tumor.

Chemotherapy for pancreatic cancer is hampered by the tumor's physio-pathological complexity. Here we show a targeted nanomedicine using a new ligand, the CKAAKN peptide, which had been identified by phage display, as an efficient homing device within the pancreatic pathological microenvironment. Taking advantage of the squalenoylation platform, the CKAAKN peptide was conjugated to squalene (SQCKAAKN) and then co-nanoprecipitated with the squalenoyl prodrug of gemcitabine (SQdFdC) giving near monodisperse nanoparticles (NPs) for safe intravenous injection. By interacting with a novel target pathway, the Wnt-2, the CKAAKN functionalization enabled nanoparticles: (i) to specifically interact with both tumor cells and angiogenic vessels and (ii) to simultaneously promote pericyte coverage, thus leading to the normalization of the vasculature likely improving the tumor accessibility for therapy. All together, this approach represents a unique targeted nanoparticle design with remarkable selectivity towards pancreatic cancer and multiple mechanisms of action.