Human vascular endothelial cells in primary cell culture for the evaluation of nanoparticle bioadhesion

Nanoparticles (NP) are employed in various therapeutic approaches for innovative drug delivery strategies. Among them, there is drug delivery to the brain and sustained release forms for intravenous drug delivery. In order to optimize drug carriers and to elucidate involved mechanisms such as bioadhesion and cellular uptake, NP were surface modified and analyzed for their interaction with human endothelial cells in cell culture. Fluorescently labeled NP of different diameters (50 to 1000 nm) were surface modified either by simple adsorption of chitosan or by covalent binding to the lectin ulex europaeus agglutinin and thereafter applied to human endothelial cells for different incubation periods. After incubation with NP the binding of NP was quantified directly by the fluorescence emission signals from the cell layers. In order to visualize the binding behaviour, NP were localized three-dimensionally in the cell layer by confocal laser scanning microscopy. Cell binding experiments in phosphate buffer were observed to be particle size dependent with the 50 nm NP showing the highest binding percentage over all experiments. Binding decreased with increasing particle diameter and shorter incubation interval. The adhesion was further enhanced by NP surface modifications in the order blank < chitosan < lectin. The presence of plasma proteins enhanced the adhesiveness of chitosan coated NP, while the binding of lectin coated NP was inhibited. Experiments at 4 degrees C indicated the involvement of an active process in the binding of NP to endothelial cells.     

Preparation of emulsifying wax/glyceryl monooleate nanoparticles and evaluation as a delivery system for repurposing simvastatin in bone regeneration

Simvastatin (Sim) is a widely known drug in the treatment of hyperlipidemia, which has attracted so much attention in bone regeneration due to its potential osteoanabolic effect. However, repurposing of Sim in bone regeneration will require suitable delivery systems that can negate undesirable off-target/side effects. In this study, we have investigated a new lipid nanoparticle (NP) platform that was fabricated using a binary blend of emulsifying wax (Ewax) and glyceryl monooleate (GMO). Using the binary matrix materials, NPs loaded with Sim (0–500?µg/mL) were prepared and showed an average particle size of about 150?nm. NP size stability was dependent on Sim concentration loaded in NPs. The suitability of NPs prepared with the binary matrix materials in Sim delivery for potential application in bone regeneration was supported by biocompatibility in pre-osteoclastic and pre-osteoblastic cells. Additional data demonstrated that biofunctional Sim was released from NPs that facilitated differentiation of osteoblasts (cells that form bones) while inhibiting differentiation of osteoclasts (cells that resorb bones). The overall work demonstrated the preparation of NPs from Ewax/GMO blends and characterization to ascertain potential suitability in Sim delivery for bone regeneration. Additional studies on osteoblast and osteoclast functions are warranted to fully evaluate the efficacy of Sim-loaded Ewax/GMO NPs using in-vitro and in-vivo approaches.     

Preparation and evaluation of N-caproyl chitosan nanoparticles surface modified with glycyrrhizin for hepatocyte targeting

Background: The development of an efficient targeted drug delivery system into cells is an important subject for the advancement of drug carriers. In this study, a novel hepatocyte-targeted delivery system with glycyrrhizin (GL) surface modification based on N-caproyl chitosan (CCS) has been developed. Method: CCS was synthesized by acylation of amino group of chitosan, and GL was oxidized to be conjugated to the surface of N-caproyl chitosan nanoparticles (CCS-NPs-GL). The synthesized nanoparticles were first characterized for their morphology, particle size, zeta potential, in vitro stability in plasma, tissue distribution, and hepatocyte-targeting uptake in vivo. Results: The obtained results showed that the spherical and discrete nanoparticles prepared with oxidized GL/CCS ratio of 0.14:1 (w/w) exhibited a positive electrical charge and associated adriamycin quite efficiently (association efficiency: 87.5%). The prepared nanoparticles also possessed dimensional and GL surface-binding stability and slow release property in plasma in vitro. The biodistribution of these particles after intravenous injections in mice revealed accumulating drug concentrations in the liver, spleen, and lungs while decreasing drug concentrations in the heart and kidney. The content of adriamycin-loaded CCS-NPs-GL in the liver was 1.6 times higher than that of non-GL-modified CCS-NPs. Furthermore, in vivo uptake of CCS-NPs-GL by rat hepatocytes showed 2.1 times higher nanoparticle uptake compared with non-GL-modified CCS-NPs, which suggested that CCS-NPs-GL were preferentially distributed in hepatocytes by a ligand–receptor interaction. Conclusion: This article indicated that CCS-NPs-GL was a stable and effective drug delivery vehicle for hepatocyte targeting.     

生物医用磁性纳米颗粒的制备与表面改性

磁性纳米颗粒目前是生物医用纳米材料领域异常活跃的方向之一.不同方法制备的磁性纳米颗粒经不同聚合物或分子表面改性后具有多方面的生物医学应用.本文综合评述了磁性纳米颗粒的制备方法,如共沉淀法、溶胶-凝胶法、微乳剂法等;总结了磁性纳米颗粒表面改性技术,包括改性物质与改性方法;概括了磁性纳米颗粒在生物医学领域的应用,主要涉及磁靶向制剂、细胞分离、肿瘤细胞的过热治疗、MR I衬度增强剂四方面.磁性纳米颗粒还有很大的发展空间和广阔的应用前景.     

Surface Functionality of Nanoparticles Determines Cellular Uptake Mechanisms in Mammalian Cells

Nanoparticles (NPs) are versatile scaffolds for numerous biomedical applications including drug delivery and bioimaging. The surface functionality of NPs essentially dictates intracellular NP uptake and controls their therapeutic action. Using several pharmacological inhibitors, it is demonstrated that the cellular uptake mechanisms of cationic gold NPs in both cancer (HeLa) and normal cells (MCF10A) strongly depend on the NP surface monolayer, and mostly involve caveolae and dynamin‐dependent pathways as well as specific cell surface receptors (scavenger receptors). Moreover, these NPs show different uptake mechanisms in cancer and normal cells, providing an opportunity to develop NPs with improved selectivity for delivery applications.     

In vitro macrophage uptake and in vivo biodistribution of PLA–PEG nanoparticles loaded with hemoglobin as blood substitutes: effect of PEG content

The aim of the present work is to investigate the effect of PEG content in copolymer on physicochemical properties, in vitro macrophage uptake, in vivo pharmacokinetics and biodistribution of poly(lactic acid) (PLA)–poly(ethylene glycol) (PEG) hemoglobin (Hb)-loaded nanoparticles (HbP) used as blood substitutes. The HbP were prepared from PLA and PLA–PEG copolymer of varying PEG contents (5, 10, and 20 wt%) by a modified w/o/w method and characterized with regard to their morphology, size, surface charge, drug loading, surface hydrophilicity, and PEG coating efficiency. The in vitro macrophage uptake, in vivo pharmacokinetics, and biodistribution following intravenous administration in mice of HbP labeled with 6-coumarin, were evaluated. The HbP prepared were all in the range of 100–200 nm with highest encapsulation efficiency 87.89%, surface charge −10 to −33 mV, static contact angle from 54.25° to 68.27°, and PEG coating efficiency higher than 80%. Compared with PLA HbP, PEGylation could notably avoid the macrophage uptake of HbP, in particular when the PEG content was 10 wt%, a minimum uptake (6.76%) was achieved after 1 h cultivation. In vivo, besides plasma, the major cumulative organ was the liver. All PLA–PEG HbP exhibited dramatically prolonged blood circulation and reduced liver accumulation, compared with the corresponding PLA HbP. The PEG content in copolymer affected significantly the survival time in blood. Optimum PEG coating (10 wt%) appeared to exist leading to the most prolonged blood circulation of PLA–PEG HbP, with a half-life of 34.3 h, much longer than that obtained by others (24.2 h). These results demonstrated that PEG 10 wt% modified PLA HbP with suitable size, surface charge, and surface hydrophilicity, has a promising potential as long-circulating oxygen carriers with desirable biocompatibility and biofunctionality.     

Shuttle‐Mediated Nanoparticle Delivery to the Blood–Brain Barrier

Many therapeutic drugs are excluded from entering the brain due to their lack of transport through the blood–brain barrier (BBB). The development of new strategies for enhancing drug delivery to the brain is of great importance in diagnostics and therapeutics of central nervous diseases. To overcome this problem, a viral fusion peptide (gH625) derived from the glycoprotein gH of Herpes simplex virus type 1 is developed, which possesses several advantages including high cell translocation potency, absence of toxicity of the peptide itself, and the feasibility as an efficient carrier for delivering therapeutics. Therefore, it is hypothesized that brain delivery of nanoparticles conjugated with gH625 should be efficiently enhanced. The surface of fluorescent aminated polystyrene nanoparticles (NPs) is functionalized with gH625 via a covalent binding procedure, and the NP uptake mechanism and permeation across in vitro BBB models are studied. At early incubation times, the uptake of NPs with gH625 by brain endothelial cells is greater than that of the NPs without the peptide, and their intracellular motion is mainly characterized by a random walk behavior. Most importantly, gH625 peptide decreases NP intracellular accumulation as large aggregates and enhances the NP BBB crossing. In summary, these results establish that surface functionalization with gH625 may change NP fate by providing a good strategy for the design of promising carriers to deliver drugs across the BBB for the treatment of brain diseases.     

Synthesis of surfactant‐modified ZIF‐8 with controllable microstructures and their drug loading and sustained release behaviour

Metal‐organic frameworks (MOFs) as drug carriers have many advantages than traditional drug carriers and have received extensive attention from researchers. However, how to regulate the microstructure of MOFs to improve the efficiency of drug delivery and sustained release behaviour is still a big problem for the clinical application. Herein, the authors synthesise surfactant‐modified ZIF‐8 nanoparticles with different microstructures by using different types of surfactants to modify ZIF‐8. The surfactant‐modified ZIF‐8 nanoparticles have the larger specific surface area and total micropore volumes than the original ZIF‐8, which enables doxorubicin (DOX) to be more effectively loaded on the drug carriers and achieve controlled drug sustained release. Excellent degradation performance of ZIF‐8 nanoparticles facilitates the metabolism of drug carriers. The formulation was evaluated for cytotoxicity, cellular uptake and intracellular location in the A549 human non‐small‐cell lung cancer cell line. ZIF‐8/DOX nano drugs exhibit higher cytotoxicity towards cells in comparison with free DOX, suggesting the potential application in nano drugs to cancer chemotherapy.Inspec keywords: nanomedicine, lung, nanofabrication, drug delivery systems, cellular biophysics, nanoparticles, cancer, toxicology, biomedical materials, drugs, organometallic compounds, surfactants, porosity, biodegradable materialsOther keywords: controlled drug sustained release, nanodrugs, controllable microstructures, drug loading, metal‐organic frameworks, traditional drug carriers, drug delivery, surfactant‐modified ZIF‐8 nanoparticles, specific surface area, micropore volumes, doxorubicin, degradation performance, metabolism, cytotoxicity, cellular uptake, intracellular location, A549 human nonsmall‐cell lung cancer cell line, cancer chemotherapy     

Controlling in vivo stability and biodistribution in electrostatically assembled nanoparticles for systemic delivery

This paper demonstrates the generation of systemically deliverable layer-by-layer (LbL) nanoparticles for cancer applications. LbL-based nanoparticles designed to navigate the body and deliver therapeutics in a programmable fashion are promising new and alternative systems for drug delivery, but there have been very few demonstrations of their systemic delivery in vivo due to a lack of knowledge in building LbL nanofilms that mimic traditional nanoparticle design to optimize delivery. The key to the successful application of these nanocarriers in vivo requires a systematic analysis of the influence of film architecture and adsorbed polyelectrolyte outer layer on their pharmacokinetics, which has thus far not been examined for this new approach to nanoparticle delivery. Herein, we have taken the first steps in stabilizing and controlling the systemic distribution of multilayer nanoparticles. Our findings highlight the unique character of LbL systems; the electrostatically assembled nanoparticles gain increased stability in vivo with larger numbers of deposited layers, and the final layer adsorbed generates a critical surface cascade, which dictates the surface chemistry and biological properties of the nanoparticle. This outer polyelectrolyte layer dramatically affects not only the degree of nonspecific particle uptake, but also the nanoparticle biodistribution. For hyaluronic acid (HA) outer layers, a long blood elimination half-life (～9 h) and low accumulation (～10-15% recovered fluorescence/g) in the liver were observed, illustrating that these systems can be designed to be highly appropriate for clinical translation.     

A generally adoptable radiotracing method for tracking carbon nanotubes in animals

Carbon nanotube (CNT) mediated drug delivery systems have currently aroused a great deal of interest. Such delivery systems for drugs, proteins and genes have been preliminarily studied using cellular and animal models. For the further study of the pharmacokinetics and related biological behaviours of CNTs in vivo, a fast and convenient tracing method is particularly demanded. In this paper, we developed a generally adoptable tracing method for the biodistribution study of functionalized CNTs in vivo. Taurine covalently functionalized multi-walled carbon nanotubes (tau-MWNTs) and Tween-80 wrapped MWNTs (Tween-MWNTs) were labelled with (125)I, and then their distribution in mice was determined. It is interesting that Tween-80 can reduce the RES uptake of MWNTs remarkably. The resulting distribution of (125)I-tau-MWNTs was very consistent with that using (14)C-taurine-MWNTs as the CNTs tracer, which means the easy (125)I labelling method is reliable and effective.     

Drug delivery devices based on macroporous silica spheres

A new kind of silica materials was proposed as carriers for drug delivery. The materials are characterized by the presence of hierarchical macro/mesopores, penetrable macropores and large pore volumes. The unique structure renders them ideal carriers for efficient and sufficient loading of drugs to establish controlled delivery systems. A series of such materials were synthesized and derivatized with octyl or octadecyl to investigate their drug delivery behavior. Nimodipine, as a model drug, was entrapped into the carriers by repeated soaking, filtration and evaporation. It is found that the drug-loading amount increased with increasing mesopore sizes of the carriers. The loading amount can reach as high as 350 wt% (drug/carrier). The in vitro release studies demonstrate that both enhanced release and sustained release can be achieved on the proposed materials. Moreover, the release speed can be controlled by the macropore sizes and surface characteristics of the materials.     

S-adenosyl-l-methionine (SAMe)-loaded nanochitosan particles: synthesis,characterisation and in vitro drug release studies

Chitosan-based drug carriers are being widely exploited for sustained and targeted delivery in cancer, anti-depression and nutritive therapeutics. In this paper, we report the preparation of S-adenosyl-l-methionine (SAMe) drug-loaded nanochitosan-based tablets and the sustained delivery of the drug substance in simulated intestinal conditions through an in vitro study. The convertibility of high molecular weight commercial chitosan to nanoparticles by ionic gelation using potassium pyrophosphate was achieved without employing harsh reaction conditions through an intermediate water-soluble chitosan preparation. The prepared nanochitosan particles with an average size of 85–127 nm showed good drug-loading capacity. In vitro release studies showed a continuous and slow release of the drug over 14 hours. Different kinetics models were applied to drug release data in order to evaluate the releasing mechanism. The drug release data fit well into the Higuchi expression, suggesting a diffusion-controlled drug delivery. The diffusional coefficient of 1.83 indicated that the drug release from the chitosan matrix was through swelling of the matrix. Agreement of the kinetic data with Higuchi and Korsmeyer–Peppas models have led us to conclude that the delivery of the SAMe drug from the nanochitosan drug carrier took place by the diffusion-controlled swelling mechanism described as Super case II transport. The prepared nanochitosan matrix was also found to be an environment-sensitive vehicle suitable for controlled drug delivery.     

Intracellular delivery of etoposide loaded biodegradable nanoparticles: cytotoxicity and cellular uptake studies

The preferred delivery systems for anticancer drugs would be the one which would have selective and effective destruction of cancer cells. In the present study etoposide (ETO) loaded nanoparticles (NP) were prepared using PLGA (ETO-PLGA NP), PLGA-MPEG block copolymer (ETO-PLGA-MPEG NP) and PLGA-Pluronic copolymer (ETO-PLGA-PLU NP) and they were evaluated for cytotoxicity and cellular uptake studies using two cancer cell lines, L1210 and DU145. The IC50 values for L1210 cells were 18.0, 6.2, 4.8 and 5.4 microM and for DU145 cells the IC50 values were 98.4, 75.1, 60.1 and 71.3 microM for ETO, ETO-PLGA NP, ETO-PLGA-MPEG NP and ETO-PLGA-PLU NP respectively. The increased cytotoxicities were attributed to increased uptake of the NPs by the cells. Moreover the ETO loaded PLGA-MPEG NP and PLGA-Pluronic NP showed a sustained cytotoxic effect till 5 days on both the cell lines. Results of the long term cytotoxicity study concluded that the drug loaded PLGA nanoparticulate formulations were efficient in decreasing the viability of the L1210 cells over a period of three days, whereas the pure drug exerted its maximum efficiency on the day one itself. Z-stack confocal images of NPs showed fluorescence activity in each section of DU 145 and L1210 cells indicating that the nanoparticles were internalized by the cells. The study concluded that ETO loaded PLGA NPs had higher cytotoxicity compared with that of the free drug and ETO-PLGA-MPEG NP and ETO-PLGA-PLU NP had higher cell uptake efficiency compared with that of ETO-PLGA NP. The developed PLGA based NPs shows promise to be used for cancer therapy.     

The Crown and the Scepter: Roles of the Protein Corona in Nanomedicine

Engineering nanomaterials are increasingly considered promising and powerful biomedical tools or devices for imaging, drug delivery, and cancer therapies, but few nanomaterials have been tested in clinical trials. This wide gap between bench discoveries and clinical application is mainly due to the limited understanding of the biological identity of nanomaterials. When they are exposed to the human body, nanoparticles inevitably interact with bodily fluids and thereby adsorb hundreds of biomolecules. A “biomolecular corona” forms on the surface of nanomaterials and confers a new biological identity for NPs, which determines the following biological events: cellular uptake, immune response, biodistribution, clearance, and toxicity. A deep and thorough understanding of the biological effects triggered by the protein corona in vivo will speed up their translation to the clinic. To date, nearly all studies have attempted to characterize the components of protein coronas depending on different physiochemical properties of NPs. Herein, recent advances are reviewed in order to better understand the impact of the biological effects of the nanoparticle–corona on nanomedicine applications. The recent development of the impact of protein corona formation on the pharmacokinetics of nanomedicines is also highlighted. Finally, the challenges and opportunities of nanomedicine toward future clinical applications are discussed.     

Gold Nanoparticle–Protein Agglomerates as Versatile Nanocarriers for Drug Delivery

The fabrication of a versatile nanocarrier based on agglomerated structures of gold nanoparticle (Au NP)–lysozyme (Lyz) in aqueous medium is reported. The carriers exhibit efficient loading capacities for both hydrophilic (doxorubicin) and hydrophobic (pyrene) molecules. The nanocarriers are finally coated with an albumin layer to render them stable and also facilitate their uptake by cancer cells. The interaction between agglomerated structures and the payloads is non‐covalent. Cell viability assay in vitro showed that the nanocarriers by themselves are non‐cytotoxic, whereas the doxorubicin‐loaded ones are cytotoxic, with efficiencies higher than that of the free drug. Transmission electron microscopy and fluorescence microscopy along with flow cytometry analysis confirm the uptake of the drug‐loaded nanocarriers by a human cervical cancer HeLa cell line. Field‐emission scanning electron microscopy reveals the formation of apoptotic bodies leading to cell death, confirming the release of the payloads from the nanocarriers into the cell. Overall, the findings suggest the fabrication of novel Au NP–protein agglomerate‐based nanocarriers with efficient drug‐loading and ‐releasing capabilities, enabling them to act as multimodal drug‐delivery vehicles.     

Immune Cell‐Mediated Biodegradable Theranostic Nanoparticles for Melanoma Targeting and Drug Delivery

Although tremendous efforts have been made on targeted drug delivery systems, current therapy outcomes still suffer from low circulating time and limited targeting efficiency. The integration of cell‐mediated drug delivery and theranostic nanomedicine can potentially improve cancer management in both therapeutic and diagnostic applications. By taking advantage of innate immune cell's ability to target tumor cells, the authors develop a novel drug delivery system by using macrophages as both nanoparticle (NP) carriers and navigators to achieve cancer‐specific drug delivery. Theranostic NPs are fabricated from a unique polymer, biodegradable photoluminescent poly (lactic acid) (BPLP‐PLA), which possesses strong fluorescence, biodegradability, and cytocompatibility. In order to minimize the toxicity of cancer drugs to immune cells and other healthy cells, an anti‐BRAF V600E mutant melanoma specific drug (PLX4032) is loaded into BPLP‐PLA nanoparticles. Muramyl tripeptide is also conjugated onto the nanoparticles to improve the nanoparticle loading efficiency. The resulting nanoparticles are internalized within macrophages, which are tracked via the intrinsic fluorescence of BPLP‐PLA. Macrophages carrying nanoparticles deliver drugs to melanoma cells via cell–cell binding. Pharmacological studies also indicate that the PLX4032 loaded nanoparticles effectively kill melanoma cells. The “self‐powered” immune cell‐mediated drug delivery system demonstrates a potentially significant advancement in targeted theranostic cancer nanotechnologies.     

Preparation,characterization, in vivo biodistribution and pharmacokinetic studies of donepezil-loaded PLGA nanoparticles for brain targeting

Objective: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder manifested by cognitive, memory deterioration and variety of neuropsychiatric symptoms. Donepezil is a reversible cholinesterase inhibitor used for the treatment of AD. The purpose of this work is to prepare a nanoparticulate drug delivery system of donepezil using poly(lactic-co-glycolic acid) (PLGA) for sustained release and efficient brain targeting.

Materials and methods: PLGA nanoparticles (NPs) were prepared by the solvent emulsification diffusion–evaporation technique and characterized for particle size, particle-size distribution, zeta potential, entrapment efficiency, drug loading and interaction studies and in vivo studies using gamma scintigraphy techniques.

Results and discussion: The size of drug-loaded NPs (drug polymer ratio 1:1) was found to be 89.67?±?6.43?nm. The TEM and SEM images of the formulation suggested that particle size was within 20–100?nm and spherical in shape, smooth morphology and coating of Tween-80 on the NPs was clearly observed. The release behavior of donepezil exhibited a biphasic pattern characterized by an initial burst release followed by a slower and continuous sustained release. The biodistribution studies of donepezil-loaded PLGA NPs and drug solution via intravenous route revealed higher percentage of radioactivity per gram in the brain for the nanoparticulate formulation as compared with the drug solution (p?Conclusion: The high concentrations of donepezil uptake in brain due to coated NPs may help in a significant improvement for treating AD. But further, more extensive clinical studies are needed to check and confirm the efficacy of the prepared drug delivery system.     

Formulation optimization and pharmacokinetics evaluation of oral self-microemulsifying drug delivery system for poorly water soluble drug cinacalcet and no food effect

The present research indicated that a new self-microemulsifying drug delivery systems (SMEDDS) were used to reduce the food effect of poorly water-soluble drug cinacalcet and enhance the bioavailability in beagle dogs by oral gavage. Ethyl oleate, OP-10, and PEG-200 was selected as the oil phase, surfactant and co-surfactant of cinacalcet-SMEDDS by the solubility and phase diagram studies. Central Composite Design-Response Surface Methodology was used to determine the ratio of surfactant and co-surfactant, the amount of oil for optimizing the SMEDDS formation. The prepared formulations were further characterized by the droplet size, self-microemulsifying time, zeta potential, polydispersity index (PDI), and robustness to dilution. The in vitro release profile of cinacalcet-SMEDDS was determined in four different release medium and in fasted state and fed state of simulated gastrointestinal fluid. Cinaclcet-SMEDDS were implemented under fed and fasted state in dogs and product REGPARA^® was used as a comparison to the prepared formulation in the pharmacokinetics. The result showed the components of SMEDDS, the amount of oil, the ratio of surfactant, and co-surfactant was optimized using solubility, pseudo-ternary phase diagram studies, and response surface methodology. In vitro drug release studies indicated that the cinacalcet-SMEDDS eliminated the effect of pH variability in release medium and variational gastroenteric environments with improved drug release performance. Pharmacokinetic studies revealed that the profiles of cinacalcet-SMEDDS were similar both in the fasted and fed state compared with commercial product, indicating the formulation significantly promoted the absorption, enhanced bioavailability and had no food effect essentially. It is concluded that poorly water-soluble drug cinacalcet was improved in the solubility and bioavailability by using a successful oral dosage form the SMEDDS, and eliminated food effect as well.     

Nanocarriers with gentamicin to treat intracellular pathogens

Brucellosis is a worldwide zoonosis caused by different species of the genus Brucella. The intracellular localisation of this pathogen, particularly in macrophages, renders treatment difficult since most antibiotics known to be efficient in vitro do not actively pass through cellular membranes. As alternative to current treatment, polymeric drug delivery systems containing gentamicin have been developed. These particulate carriers target the drug into the mononuclear-phagocytic system, where the pathogen resides that will allow intracellular accumulation of the antibiotic after particle degradation. Besides, particle uptake may induce macrophage activation, increasing the production of reactive oxygen intermediates, involved in host defense against the intracellular pathogen. The aim of the present work was to study the suitability of polymeric nanoparticles for gentamicin entrapment in view to treat brucellosis. Different poly(lactide-co-glycolide) PLGA polymers were used to formulate the nanoparticles containing gentamicin by a water-oil-water solvent evaporation method. Furthermore, in vitro macrophage activation upon nanoparticles phagocytosis and in vivo distribution of the nanocarriers in the target organs for Brucella (liver and spleen) were also studied. The nanoparticle sizes were below 350 nm, the gentamicin encapsulation efficiency depended on the polymer type used for their preparation and the in vitro release of the antibiotic exhibited a continuos pattern (PLGA 502H). PLGA 502H nanoparticles were the most suitable due to the highest entrapment and the most sustained release. The nanoparticles were successfully phagocyted by a J774 murine monocytes cell line and biodistribution studies in mice after intravenous administration of the delivery systems revealed that the particles reached the target organs of Brucella (liver and spleen). All together, these results indicate that the nanocarriers described in this work may be suitable as gentamicin delivery system to control brucellosis.     

Engineered Multifunctional Albumin‐Decorated Porous Silicon Nanoparticles for FcRn Translocation of Insulin

The last decade has seen remarkable advances in the development of drug delivery systems as alternative to parenteral injection‐based delivery of insulin. Neonatal Fc receptor (FcRn)‐mediated transcytosis has been recently proposed as a strategy to increase the transport of drugs across the intestinal epithelium. FcRn‐targeted nanoparticles (NPs) could hijack the FcRn transcytotic pathway and cross the epithelial cell layer. In this study, a novel nanoparticulate system for insulin delivery based on porous silicon NPs is proposed. After surface conjugation with albumin and loading with insulin, the NPs are encapsulated into a pH‐responsive polymeric particle by nanoprecipitation. The developed NP formulation shows controlled size and homogeneous size distribution. Transmission electron microscopy (TEM) images show successful encapsulation of the NPs into pH‐sensitive polymeric particles. No insulin release is detected at acidic conditions, but a controlled release profile is observed at intestinal pH. Toxicity studies show high compatibility of the NPs with intestinal cells. In vitro insulin permeation across the intestinal epithelium shows approximately fivefold increase when insulin is loaded into FcRn‐targeted NPs. Overall, these FcRn‐targeted NPs offer a toolbox in the development of targeted therapies for oral delivery of insulin.