Evaluation of Two Osmosis-Based Methods for the Preparation of Drug Delivery Systems Based on Red Blood Cells.

Erythrocytes have been thoroughly investigated as drug delivery systems for a wide range of therapeutic molecules and using different kinds of loading methods, outstanding the osmosis-based methods as the most used ones. Most of them involve too much handling of blood components and the immediate obtention of fresh blood. Based on our group's considerable experience in dialysis-based carrier erythrocyte preparation, this study details a simple method based on hypotonic dilution and subsequent resealing that has been developed for stavudine using packed erythrocytes from a local blood bank. Properties of the obtained carrier erythrocytes were studied in comparison to those prepared by dialysis. Erythrocytes' morphology, osmotic fragility, hematological parameters, and in vitro release profiles were evaluated. Loaded erythrocytes obtained with the proposed method did not show impaired properties in comparison with those obtained with our reference method, provided that the buffer composition remained the same. In the present work, we have optimized a simplified method for erythrocytes' drug loading, which can use blood transfusion products and could be easily automatized and scalable.

Physiologically Based Pharmacokinetic (PBPK) Model of Gold Nanoparticle-Based Drug Delivery System for Stavudine Biodistribution.

Computational modelling has gained attention for evaluating nanoparticle-based drug delivery systems. Physiologically based pharmacokinetic (PBPK) modelling provides a mechanistic approach for evaluating drug biodistribution. The aim of this work is to develop a specific PBPK model to simulate stavudine biodistribution after the administration of a 40 nm gold nanoparticle-based drug delivery system in rats. The model parameters used have been obtained from literature, in vitro and in vivo studies, and computer optimization. Based on these, the PBPK model was built, and the compartments included were considered as permeability rate-limited tissues. In comparison with stavudine solution, a higher biodistribution of stavudine into HIV reservoirs and the modification of pharmacokinetic parameters such as the mean residence time (MRT) have been observed. These changes are particularly noteworthy in the liver, which presents a higher partition coefficient (from 0.27 to 0.55) and higher MRT (from 1.28 to 5.67 h). Simulated stavudine concentrations successfully describe these changes in the in vivo study results. The average fold error of predicted concentrations after the administration of stavudine-gold nanoparticles was within the 0.5-2-fold error in all of the tissues. Thus, this PBPK model approach may help with the pre-clinical extrapolation to other administration routes or the species of stavudine gold nanoparticles.

Recent advances in functionalized nanomaterials for the diagnosis and treatment of bacterial infections.

The growing problem of resistant infections due to antibiotic misuse is a worldwide concern that poses a grave threat to healthcare systems. Thus, it is necessary to discover new strategies to combat infectious diseases. In this review, we provide a selective overview of recent advances in the use of nanocomposites as alternatives to antibiotics in antimicrobial treatments. Metals and metal oxide nanoparticles (NPs) have been associated with inorganic and organic supports to improve their antibacterial activity and stability as well as other properties. For successful antibiotic treatment, it is critical to achieve a high drug concentration at the infection site. In recent years, the development of stimuli-responsive systems has allowed the vectorization of antibiotics to the site of infection. These nanomaterials can be triggered by various mechanisms (such as changes in pH, light, magnetic fields, and the presence of bacterial enzymes); additionally, they can improve antibacterial efficacy and reduce side effects and microbial resistance. To this end, various types of modified polymers, lipids, and inorganic components (such as metals, silica, and graphene) have been developed. Applications of these nanocomposites in diverse fields ranging from food packaging, environment, and biomedical antimicrobial treatments to diagnosis and theranosis are discussed.

A Micellar Formulation of Quercetin Prevents Cisplatin Nephrotoxicity.

The antioxidant flavonoid quercetin has been shown to prevent nephrotoxicity in animal models and in a clinical study and is thus a very promising prophylactic candidate under development. Quercetin solubility is very low, which handicaps clinical application. The aim of this work was to study, in rats, the bioavailability and nephroprotective efficacy of a micellar formulation of Pluronic F127-encapsulated quercetin (P-quercetin), with improved hydrosolubility. Intraperitoneal administration of P-quercetin leads to an increased plasma concentration and bioavailability of quercetin compared to the equimolar administration of natural quercetin. Moreover, P-quercetin retains overall nephroprotective properties, and even slightly improves some renal function parameters, when compared to natural quercetin. Specifically, P-quercetin reduced the increment in plasma creatinine (from 3.4 ± 0.5 to 1.2 ± 0.3 mg/dL) and urea (from 490.9 ± 43.8 to 184.1 ± 50.1 mg/dL) and the decrease in creatinine clearance (from 0.08 ± 0.02 to 0.58 ± 0.19 mL/min) induced by the nephrotoxic chemotherapeutic drug cisplatin, and it ameliorated histological evidence of tubular damage. This new formulation with enhanced kinetic and biopharmaceutical properties will allow for further exploration of quercetin as a candidate nephroprotector at lower dosages and by administration routes oriented towards its clinical use.

Advances in Exosomes-Based Drug Delivery Systems.

Exosomes, a subgroup of extracellular vesicles, are important mediators of long-distance intercellular communication and are involved in a diverse range of biological processes such as the transport of lipids, proteins, and nucleic acids. Researchers, seeing the problems caused by the toxic effects and clearance of synthetic nanoparticles, consider exosomes as an interesting alternative to such nanoparticles in the specific and controlled transport of drugs. In recent years, there have been remarkable advances in the use of exosomes in cancer therapeutics or for treating neurological diseases, among other applications. The objective of this work is to analyze studies focused on exosomes used in drug delivery system, present and future applications in this field of research are discussed based on the results obtained.

Cell-Based Drug Delivery Platforms.

Within the framework of nanomedicine, drug delivery has experienced rapid progress in recent years [...].

Targeting of Hepatic Macrophages by Therapeutic Nanoparticles.

Hepatic macrophage populations include different types of cells with plastic properties that can differentiate into diverse phenotypes to modulate their properties in response to different stimuli. They often regulate the activity of other cells and play an important role in many hepatic diseases. In response to those pathological situations, they are activated, releasing cytokines and chemokines; they may attract circulating monocytes and exert functions that can aggravate the symptoms or drive reparation processes. As a result, liver macrophages are potential therapeutic targets that can be oriented toward a variety of aims, with emergent nanotechnology platforms potentially offering new perspectives for macrophage vectorization. Macrophages play an essential role in the final destination of nanoparticles (NPs) in the organism, as they are involved in their uptake and trafficking in vivo. Different types of delivery nanosystems for macrophage recognition and targeting, such as liposomes, solid-lipid, polymeric, or metallic nanoparticles, have been developed. Passive targeting promotes the accumulation of the NPs in the liver due to their anatomical and physiological features. This process is modulated by NP characteristics such as size, charge, and surface modifications. Active targeting approaches with specific ligands may also be used to reach liver macrophages. In order to design new systems, the NP recognition mechanism of macrophages must be understood, taking into account that variations in local microenvironment may change the phenotype of macrophages in a way that will affect the uptake and toxicity of NPs. This kind of information may be applied to diseases where macrophages play a pathogenic role, such as metabolic disorders, infections, or cancer. The kinetics of nanoparticles strongly affects their therapeutic efficacy when administered in vivo. Release kinetics could predict the behavior of nanosystems targeting macrophages and be applied to improve their characteristics. PBPK models have been developed to characterize nanoparticle biodistribution in organs of the reticuloendothelial system (RES) such as liver or spleen. Another controversial issue is the possible toxicity of non-degradable nanoparticles, which in many cases accumulate in high percentages in macrophage clearance organs such as the liver, spleen, and kidney.

Cell-based drug-delivery platforms.

Cell systems have recently emerged as biological drug carriers, as an interesting alternative to other systems such as micro- and nano-particles. Different cells, such as carrier erythrocytes, bacterial ghosts and genetically engineered stem and dendritic cells have been used. They provide sustained release and specific delivery of drugs, enzymatic systems and genetic material to certain organs and tissues. Cell systems have potential applications for the treatment of cancer, HIV, intracellular infections, cardiovascular diseases, Parkinson's disease or in gene therapy. Carrier erythrocytes containing enzymes such us L-asparaginase, or drugs such as corticosteroids have been successfully used in humans. Bacterial ghosts have been widely used in the field of vaccines and also with drugs such as doxorubicin. Genetically engineered stem cells have been tested for cancer treatment and dendritic cells for immunotherapeutic vaccines. Although further research and more clinical trials are necessary, cell-based platforms are a promising strategy for drug delivery.

In vitro studies of amikacin-loaded human carrier erythrocytes.

Erythrocyte-encapsulated antibiotics have the potential to provide an effective therapy against intracellular pathogens. The advantages over the administration of free antibiotics include a lower systemic dose, decreased toxicity, a sustained delivery of the antibiotic at higher concentrations to the intracellular site of pathogen replication, and increased efficacy. In this study, the encapsulation of amikacin by human carrier erythrocytes prepared using a hypo-osmotic dialysis was investigated. The effects of the initial amikacin dialysis concentration and hypo-osmotic dialysis time on the encapsulation efficiency of amikacin were determined, and the osmotic fragility and hematologic parameters of amikacin-loaded carrier erythrocytes were measured. The efficiency of amikacin entrapment by carrier erythrocytes was dependent on the initial dialysis concentration of the drug. Statistically significant differences in the osmotic fragility profiles between control and carrier erythrocytes were observed, which were dependent on the hypo-osmotic dialysis time and on the dialysis concentration of amikacin. Mean hematologic parameters were evaluated and compared with unloaded, native erythrocytes; the mean corpuscular volume (MCV) of amikacin-loaded carrier erythrocytes was statistically significant smaller. Amikacin demonstrated a sustained release from loaded erythrocytes over a 48-h period, which suggests a potential use of the erythrocyte as a slow systemic-release system for antibiotics.

Pharmacokinetics and biodistribution of amikacin encapsulated in carrier erythrocytes.

OBJECTIVES: To study the changes in the pharmacokinetics and tissue distribution of the aminoglycoside amikacin in rats using amikacin carrier erythrocytes as a delivery system. METHODS: Amikacin-loaded erythrocytes were obtained using a hypotonic dialysis method. The pharmacokinetic and tissue distribution of amikacin were studied in three groups of rats receiving intravenous amikacin in saline solution, amikacin-loaded erythrocytes and amikacin-loaded erythrocytes treated with glutaraldehyde. Pharmacokinetic analysis was accomplished using model-independent methods. RESULTS: Administration of the antibiotic using carrier erythrocytes elicited a sustained release effect, with an increase in the plasma half-life and in the area under the curve of the antibiotic. The tissue pharmacokinetics of amikacin using carrier erythrocytes in comparison with a control group revealed an accumulation of the antibiotic in specific tissues such as the liver and spleen, a similar pharmacokinetics in the lung and moderate changes in the pharmacokinetics in the kidney. Studies of tissue concentrations after the injection of glutaraldehyde-treated loaded erythrocytes demonstrated important changes in organs of the reticulo-endothelial system (RES) in comparison with the results observed for standard carrier erythrocytes, higher levels being observed in the liver whereas spleen levels decreased. CONCLUSIONS: The administration of amikacin in loaded erythrocytes in rats leads to significant changes in the pharmacokinetic behaviour of the antibiotic, a greater accumulation being observed in RES organs such as liver and spleen. This shows that loaded erythrocytes are potentially useful for the delivery of antibiotics in phagocytic cells located in the RES.

Factors associated with the performance of carrier erythrocytes obtained by hypotonic dialysis.

Carrier erythrocytes containing drugs, enzymes or peptides can be used as a delivery system that allows changes in the kinetic behaviour and selective biodistribution of the substances encapsulated. Hypotonic dialysis is the method most commonly used in the preparation of carrier erythrocytes, but many factors affect the yield and characteristics of the ghost erythrocytes obtained using this method. This review analyses the factors that affect the performance of carrier erythrocytes prepared by hypotonic dialysis. Factors such as the composition and osmolality range of the hypotonic buffer used, the duration of the hypotonic dialysis, temperature, the volume ratio between the erythrocyte suspension and the dialysis buffer, the inclusion in the process of an annealing phase, the composition and osmolality of the resealing buffer, and the conditions under which the final washing of the erythrocytes is carried out may all affect the morphological properties and the later in vivo behaviour of the ghost erythrocytes obtained. Changes in the yield of the encapsulation process, the in vitro drug or enzyme controlled delivery, the pharmacokinetic properties or the in vivo tissue targeting may be modified depending on the conditions under which the preparation of carrier erythrocytes by hypotonic dialysis is carried out. Chemical alterations to the membrane of carrier erythrocytes obtained by hypotonic dialysis with substances such as glutaraldehyde, band 3 cross-linking reagents, trypsin or NHS-biotin, among others, may affect the release rate of the substances encapsulated and may increase the uptake of cells by macrophages both in vitro and in vivo.