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.

Nanoparticles for Signaling in Biodiagnosis and Treatment of Infectious Diseases.

Advances in nanoparticle-based systems constitute a promising research area with important implications for the treatment of bacterial infections, especially against multidrug resistant strains and bacterial biofilms. Nanosystems may be useful for the diagnosis and treatment of viral and fungal infections. Commercial diagnostic tests based on nanosystems are currently available. Different methodologies based on nanoparticles (NPs) have been developed to detect specific agents or to distinguish between Gram-positive and Gram-negative microorganisms. Also, biosensors based on nanoparticles have been applied in viral detection to improve available analytical techniques. Several point-of-care (POC) assays have been proposed that can offer results faster, easier and at lower cost than conventional techniques and can even be used in remote regions for viral diagnosis. Nanoparticles functionalized with specific molecules may modulate pharmacokinetic targeting recognition and increase anti-infective efficacy. Quorum sensing is a stimuli-response chemical communication process correlated with population density that bacteria use to regulate biofilm formation. Disabling it is an emerging approach for combating its pathogenicity. Natural or synthetic inhibitors may act as antibiofilm agents and be useful for treating multi-drug resistant bacteria. Nanostructured materials that interfere with signal molecules involved in biofilm growth have been developed for the control of infections associated with biofilm-associated infections.

Gold Nanocarriers for Macrophage-Targeted Therapy of Human Immunodeficiency Virus.

The human immunodeficiency virus (HIV) continues to be a global pandemic and there is an urgent need for innovative treatment. Immune cells represent a major target of virus infection, but are also therapeutic targets. Currently, no antiretroviral therapy targets macrophages, which function as portal of entry and as major long-term deposit of HIV. It has been shown before that human macrophages efficiently internalize gold nanoparticles, a fact which might be used to target them with drug-nanoparticle conjugates. Here, the authors use gold nanocarriers to facilitate delivery of stavudine, a widely used antiretroviral drug, to primary human macrophages. Using an ease-of-use coupling method, a striking potentiation of stavudine intake by macrophages using gold nanocarriers is shown. Further, the carriers induce a specific subtype of proinflammatory activation indicative for antiviral activity of macrophages, which suggests promising novel treatment options for HIV.

Current applications of nanoparticles in infectious diseases.

For decades infections have been treated easily with drugs. However, in the 21st century, they may become lethal again owing to the development of antimicrobial resistance. Pathogens can become resistant by means of different mechanisms, such as increasing the time they spend in the intracellular environment, where drugs are unable to reach therapeutic levels. Moreover, drugs are also subject to certain problems that decrease their efficacy. This requires the use of high doses, and frequent administrations must be implemented, causing adverse side effects or toxicity. The use of nanoparticle systems can help to overcome such problems and increase drug efficacy. Accordingly, there is considerable current interest in their use as antimicrobial agents against different pathogens like bacteria, virus, fungi or parasites, multidrug-resistant strains and biofilms; as targeting vectors towards specific tissues; as vaccines and as theranostic systems. This review begins with an overview of the different types and characteristics of nanoparticles used to deliver drugs to the target, followed by a review of current research and clinical trials addressing the use of nanoparticles within the field of infectious diseases.

Study of the factors influencing the encapsulation of zidovudine in rat erythrocytes.

Antiretroviral-loaded erythrocytes offer a promising therapy against HIV owing to their potential to deliver this kind of drugs to macrophages and reticulo-endothelial (RES) tissues. The aim of the present work was to develop and optimize a hypotonic dialysis method for the encapsulation of the antiretroviral Zidovudine (AZT) in rat erythrocytes. The influence of several factors in the encapsulation was also evaluated. Variables such as the initial AZT concentration, the dialysis time, and the dialysis bag/buffer volume ratio exhibited statistically significant differences in the encapsulation of the drug in erythrocytes. The amount of drug encapsulated was related to the different values of the variables by multiple linear regression. Osmotic fragility and haematological parameters were estimated as indicators of erythrocyte viability. No statistically significant differences in the osmotic fragility profiles of the control and carrier erythrocytes were observed, and this parameter was also independent of the dialysis concentration of AZT, the hypo-osmotic dialysis time, and the dialysis bag/buffer volume ratio. The in vitro release of AZT from carrier erythrocytes pointed to a fast leakage of the drug; however, around 30% of the drug remained encapsulated for a prolonged period of time. Pre-dialysis diamide treatment did not have a significant effect on the encapsulation and release of AZT in erythrocytes.

Recent advances in delivery systems for anti-HIV1 therapy.

In the last years, different non-biological and biological carrier systems have been developed for anti-HIV1 therapy. Liposomes are excellent potential anti-HIV1 carriers that have been tested with drugs, antisense oligonucleotides, ribozymes and therapeutic genes. Nanoparticles and low-density lipoproteins (LDLs) are cell-specific transporters of drugs against macrophage-specific infections such as HIV1. Through a process of protein transduction, cell-permeable peptides of natural origin or designed artificially allow the delivery of drugs and genetic material inside the cell. Erythrocyte ghosts and bacterial ghosts are a promising delivery system for therapeutic peptides and HIV vaccines. Of interest are the advances made in the field of HIV gene therapy by the use of autologous haematopoietic stem cells and viral vectors for HIV vaccines. Although important milestones have been reached in the development of carrier systems for the treatment of HIV, especially in the field of gene therapy, further clinical trials are required so that the efficiency and safety of these new systems can be guaranteed in HIV patients.