The problems associated with drug delivery and achievement of therapeutic blood levels in neonates are reviewed, using chloramphenicol as an example. Administration of small volumes, concentrated solutions and intravenous line filter chambers greatly affect the final dose delivered to the infant. Once delivered, variability in drug elimination caused by changing hepatic and renal function and protein binding necessitate careful drug monitoring and pharmacokinetic analysis especially with drugs like chloramphenicol that have a narrow therapeutic range. If one uses a team approach involving nurses, clinical chemists and clinical pharmacologists, optimal doses of chloramphenicol in the newborn are achieved more consistently.

Intravascular triggered drug delivery systems (IV-DDS) for local drug delivery include various stimuli-responsive nanoparticles that release the associated agent in response to internal (e.g., pH, enzymes) or external stimuli (e.g., temperature, light, ultrasound, electromagnetic fields, X-rays). We developed a computational model to simulate IV-DDS drug delivery, for which we quantified all model parameters in vivo in rodent tumors. The model was validated via quantitative intravital microscopy studies with unencapsulated fluorescent dye, and with two formulations of temperature-sensitive liposomes (slow, and fast release) encapsulating a fluorescent dye as example IV-DDS. Tumor intra- and extravascular dye concentration dynamics were extracted from the intravital microscopy data by quantitative image processing, and were compared to computer model results. Via this computer model we explain IV-DDS delivery kinetics and identify parameters of IV-DDS, of drug, and of target tissue for optimal delivery. Two parameter ratios were identified that exclusively dictate how much drug can be delivered with IV-DDS, indicating the importance of IV-DDS with fast drug release (~sec) and choice of a drug with rapid tissue uptake (i.e., high first-pass extraction fraction). The computational model thus enables engineering of improved future IV-DDS based on tissue parameters that can be quantified by imaging.

α-Mangostin, a xanthone derivative from the pericarp of Garcinia mangostana L., has numerous bioactivities and pharmacological properties. However, α-mangostin has low aqueous solubility and poor target selectivity in the human body. Recently, nanoparticle drug delivery systems have become an excellent technique to improve the physicochemical properties and effectiveness of drugs. Therefore, many efforts have been made to overcome the limitations of α-mangostin through nanoparticle formulations. Our review aimed to summarise and discuss the nanoparticle drug delivery systems for α-mangostin from published papers recorded in Scopus, PubMed and Google Scholar. We examined various types of nanoparticles for α-mangostin to enhance water solubility, provide controlled release and create targeted delivery systems. These forms include polymeric nanoparticles, nanomicelles, liposomes, solid lipid nanoparticles, nanofibers and nanoemulsions. Notably, nanomicelle modification increased α-mangostin solubility increased more than 10,000 fold. Additionally, polymeric nanoparticles provided targeted delivery and significantly enhanced the biodistribution of α-mangostin into specific organs. In conclusion, the nanoparticle drug delivery system could be a promising technique to increase the solubility, selectivity and efficacy of α-mangostin as a new drug candidate in clinical therapy.

Nanoparticles have been extensively used as carriers for the delivery of chemicals and biomolecular drugs, such as anticancer drugs and therapeutic proteins. Natural biomolecules, such as proteins, are an attractive alternative to synthetic polymers commonly used in nanoparticle formulation because of their safety. In general, protein nanoparticles offer many advantages, such as biocompatibility and biodegradability. Moreover, the preparation of protein nanoparticles and the corresponding encapsulation process involved mild conditions without the use of toxic chemicals or organic solvents. Protein nanoparticles can be generated using proteins, such as fibroins, albumin, gelatin, gliadine, legumin, 30Kc19, lipoprotein, and ferritin proteins, and are prepared through emulsion, electrospray, and desolvation methods. This review introduces the proteins used and methods used in generating protein nanoparticles and compares the corresponding advantages and disadvantages of each.

Within tumors, Cancer Stem Cell (CSC) subpopulation has an important role in maintaining growth and dissemination while preserving high resistance against current treatments. It has been shown that, when CSCs are eliminated, the surrounding Differentiated Cancer Cells (DCCs) may reverse their phenotype and gain CSC-like features to preserve tumor progression and ensure tumor survival. This strongly suggests the existence of paracrine communication within tumor cells. It is evidenced that the molecular crosstalk is at least partly mediated by Extracellular Vesicles (EVs), which are cell-derived membranous nanoparticles that contain and transport complex molecules that can affect and modify the biological behavior of distal cells and their molecular background. This ability of directional transport of small molecules prospects EVs as natural Drug Delivery Systems (DDS). EVs present inherent homing abilities and are less immunogenic than synthetic nanoparticles, in general. Currently, strong efforts are focused into the development and improvement of EV-based DDS. Even though EV-DDS have already reached early phases in clinical trials, their clinical application is still far from commercialization since protocols for EVs loading, modification and isolation need to be standardized for large-scale production. Here, we summarized recent knowledge regarding the use of EVs as natural DDS against CSCs and cancer resistance.

The ISPR was initially created to monitor the product performance of Medtronic implanted intrathecal drug infusion and spinal cord systems available in the United States.

The nasal drug delivery route has distinct advantages, such as high bioavailability, a rapid therapeutic effect, non-invasiveness, and ease of administration. This article presents the results of a study of the processes for obtaining chitosan aerogel particles that are promising as nasal or inhalation drug delivery systems. Obtaining chitosan aerogel particles includes the following steps: the preparation of a chitosan solution, gelation, solvent replacement, and supercritical drying. Particles of chitosan gels were obtained by spraying and homogenization. The produced chitosan aerogel particles had specific surface areas of up to 254 m2/g, pore volumes of up to 1.53 cm3/g, and porosities of up to 99%. The aerodynamic diameters of the obtained chitosan aerogel particles were calculated, the values of which ranged from 13 to 59 µm. According to the calculation results, a CS1 sample was used as a matrix for obtaining the pharmaceutical composition "chitosan aerogel-clomipramine". X-ray diffraction (XRD) analysis of the pharmaceutical composition determined the presence of clomipramine, predominantly in an amorphous form. Analysis of the high-performance liquid chromatography (HPLC) data showed that the mass loading of clomipramine was 35%. Experiments in vivo demonstrated the effectiveness of the pharmaceutical composition "chitosan aerogel-clomipramine" as carrier matrices for the targeted delivery of clomipramine by the "Nose-to-brain" mechanism of nasal administration. The maximum concentration of clomipramine in the frontal cortex and hippocampus was reached 30 min after administration.

Gelatin is a highly versatile natural polymer, which is widely used in healthcare-related sectors due to its advantageous properties, such as biocompatibility, biodegradability, low-cost, and the availability of exposed chemical groups. In the biomedical field, gelatin is used also as a biomaterial for the development of drug delivery systems (DDSs) due to its applicability to several synthesis techniques. In this review, after a brief overview of its chemical and physical properties, the focus is placed on the commonly used techniques for the development of gelatin-based micro- or nano-sized DDSs. We highlight the potential of gelatin as a carrier of many types of bioactive compounds and its ability to tune and control select drugs' release kinetics. The desolvation, nanoprecipitation, coacervation, emulsion, electrospray, and spray drying techniques are described from a methodological and mechanistic point of view, with a careful analysis of the effects of the main variable parameters on the DDSs' properties. Lastly, the outcomes of preclinical and clinical studies involving gelatin-based DDSs are thoroughly discussed.

Ischemic stroke is a leading cause of death and disability in the world. At present, reperfusion therapy and neuroprotective therapy, as guidelines for identifying effective and adjuvant treatment methods, are limited by treatment time windows, drug bioavailability, and side effects. Nanomaterial-based drug delivery systems have the characteristics of extending half-life, increasing bioavailability, targeting drug delivery, controllable drug release, and low toxicity, thus being used in the treatment of ischemic stroke to increase the therapeutic effects of drugs. Therefore, this review provides a comprehensive overview of nanomaterial-based drug delivery systems from nanocarriers, targeting ligands and stimulus factors of drug release, aiming to find the best combination of nanomaterial-based drug delivery systems for ischemic stroke. Finally, future research areas on nanomaterial-based drug delivery systems in ischemic stroke and the implications of the current knowledge for the development of novel treatment for ischemic stroke were identified.

Diminazene aceturate is a trypanocide with unwanted toxicity and limited efficacy. It was reasoned that conjugating diminazene aceturate to functionalized nanoparticle would lower untoward toxicity while improving selectivity and therapeutic efficacy. Silver and gold nanoparticles were evaluated for their capacities to serve as carriers for diminazene aceturate. The silver and gold nanoparticles were synthesized, functionalized and coupled to diminazene aceturate following established protocols. The nanoparticle conjugates were characterized. The free diminazene aceturate and drug conjugated nanoparticles were subsequently evaluated for cytotoxicity in vitro. The characterizations by transmission electron microscopy or UV/Vis spectroscopy revealed that conjugation of diminazene aceturate to silver or gold nanoparticles was successful. Evaluation for cytotoxic actions in vitro demonstrated no significance difference between free diminazene aceturate and the conjugates. Our data suggest that surface modified metal nanoparticles could be optimized for drug delivery systems.

Poly(lactic-co-glycolic acid) (PLGA) is a biocompatible and biodegradable polymer that recently attracted attention for use as part of drug delivery systems (DDS). In this context, there is an emerging need for a rapid, reliable and reproducible method of synthesis. Here, microfluidic systems provide great opportunities for synthesizing carriers in a tightly controlled manner and with low consumption of materials, energy and time. These miniature devices have been the focus of recent research since they can address the challenges inherent to the bulk system, e.g. low drug loading efficiency and encapsulation, broad size distribution and burst initial release. In this article, we provide an overview of current microfluidic systems used in drug delivery production, with a special focus on PLGA-based DDS. In this context, we highlight the advantages associated with the use of microchip systems in the fabrication of nanoparticles (NPs) and microparticles (MPs), e.g. in achieving complex morphologies. Furthermore, we discuss the challenges for selecting proper microfluidics for targeted DDS production in a translational setting and introduce strategies that are used to overcome microfluidics shortcomings, like low throughput for production.

Intrathecal drug delivery is an effective pain management option for patients with chronic and cancer pain. The delivery of drugs into the intrathecal space provides superior analgesia with smaller doses of analgesics to minimize side effects while significantly improving quality of life. This article aims to provide a general overview of the use of intrathecal drug delivery to manage pain, dosing recommendations, potential risks and complications, and growing trends in the field.

Macrophages have been extensively used in the development of drug delivery systems, as they can prolong the circulation and release of drugs, extend their half-life, increase their stability and targeting ability, and reduce immunogenicity. Moreover, they have good biocompatibility and degradability and offer abundant surface receptors for targeted delivery of a wide variety of drugs. Macrophage-mediated drug delivery systems can be prepared by loading drugs or drug-loaded nanoparticles into macrophages, macrophage membranes or macrophage-derived vesicles. Although such systems can be used to treat inflammation, cancer, HIV infection and other diseases, they require further research and optimization since they have been assembled from diverse sources and therefore can have quite different physical and chemical properties. Moreover, potential cell-drug interactions can limit their application, and the biological activity of membrane proteins might be lost during membrane extraction and storage. In this review, we summarize the recent advances in this field and discuss the preparation of macrophage-mediated drug delivery systems, their advantages over other delivery systems, their potential applications and future lines of research.

Despite continual progress in the technologies and regimens for cancer therapy, the treatment outcome of fatal metastatic breast cancer is far from satisfactory. Encouragingly, nanotechnology has emerged as a valuable tool to optimize drug delivery process in cancer therapy via preventing the cargos from degradation, improving the tumor-targeting efficiency, enhancing therapeutic agents' retention in specific sites, and controlling drug release. In the last decade, several mechanisms of suppressing tumor metastasis by functional nano drug delivery systems (NDDSs) have been revealed and a guidance for the rational design of anti-metastasis NDDSs is summarized, which consist of three aspects: optimization of physiochemical properties, tumor microenvironment remodeling, and biomimetic strategies. A series of medicinal functional biomaterials and anti-metastatic breast cancer NDDSs constructed by our team are introduced in this review. It is hoped that better anti-metastasis strategies can be inspired and applied in clinic.

A novel chitosan-dipeptide hydrogel was fabricated through a combination of self-assembly of 9-fluorenylmethoxycarbonyl-modified diphenylalanine (Fmoc-FF) and its electrostatic interaction with glycol chitosan (GCS). Hydrogel strength and stability depended on its composition. The highest gel strength was observed at a Fmoc-FF mass fraction (ϕFF) of 0.85, whereby the highest combined strength of the two interactions was achieved. As the ϕFF increased above 0.6, gel stability decreased in buffered solution at pH 7.46. The incorporation of doxorubicin (DOX) as a cationic model drug significantly increased the stability of the complex hydrogels. DOX-loaded hydrogels exhibited slow DOX release, probably due to the drug's strong binding to Fmoc-FF via electrostatic attraction and the high gel stability. These hydrogels also exhibited excellent thixotropic features that facilitated the development of injectable self-healing drug delivery systems. Notably, DOX release was significantly accelerated as the pH of the medium decreased from 7.46 to 5.5 and 4.0, possibly due to hydrogel components' protonation. The DOX-loaded hydrogel exhibited notable cytotoxicity against A549 human lung cancer cells, which suggests the newly developed hydrogel to be a promising candidate vehicle for the localized and controlled drug delivery in cancer therapy.

The growth of microbial multidrug resistance is a problem in modern clinical medicine. Chemical modification of active pharmaceutical ingredients is an attractive strategy to improve their biopharmaceutical properties by increasing bioavailability and reducing drug toxicity. Conjugation of antimicrobial drugs with natural polysaccharides provides high efficiency of these systems due to targeted delivery, controlled drug release and reduced toxicity. This paper reports a two-step synthesis of colistin conjugates (CT) with succinyl chitosan (SucCS); first, we modified chitosan with succinyl anhydride to introduce a carboxyl function into the polymer molecule, which was then used for chemical grafting with amino groups of the peptide antibiotic CT using carbodiimide chemistry. The resulting polymeric delivery systems had a degree of substitution (DS) by CT of 3-8%, with conjugation efficiencies ranging from 54 to 100% and CT contents ranging from 130-318 μg/mg. The size of the obtained particles was 100-200 nm, and the ζ-potential varied from -22 to -28 mV. In vitro release studies at pH 7.4 demonstrated ultra-slow hydrolysis of amide bonds, with a CT release of 0.1-0.5% after 12 h; at pH 5.2, the hydrolysis rate slightly increased; however, it remained extremely low (1.5% of CT was released after 12 h). The antimicrobial activity of the conjugates depended on the DS. At DS 8%, the minimum inhibitory concentration (MIC) of the conjugate was equal to the MIC of native CT (1 µg/mL); at DS of 3 and 5%, the MIC increased 8-fold. In addition, the developed systems reduced CT nephrotoxicity by 20-60%; they also demonstrated the ability to reduce bacterial lipopolysaccharide-induced inflammation in vitro. Thus, these promising CT-SucCS conjugates are prospective for developing safe and effective nanoantibiotics.

In the past few decades, scientists have actively worked on developing effective drug delivery systems (DDSs) as means to control life-threatening diseases and challenging illnesses. In order to develop such DDSs, nanobiotechnological strategies have been introduced, and many nanomaterial-based DDS platforms have been proposed. Among these nanomaterials, DDSs based on exosomes and hybrids of exosomes have been focused upon and developed due to their low toxicity, high bioactivity, and biocompatibility. In this review, we describe the processes involved in drug loading into exosomes and the surface modification of exosomes with treatment agents. Furthermore, we describe the synthesis methods of hybrid exosomes with organic or inorganic nanoparticles. Moreover, we focus on the effective therapeutic applications of exosome-based DDSs against various diseases. In conclusion, we show that exosomes and hybrids of exosomes show excellent drug carrier potential and capacity.

This research concerns the investigation of the preparation of polymeric nanocarriers containing a flavonoid-naringenin, xanthohumol or isoxanthohumol-based on Pluronics by the thin-film formation method. The size of the formed micelles and their stability upon dilution were evaluated using Dynamic light scattering (DLS) analysis; the high values of the drug loading and the encapsulation efficiency confirmed that the proposed systems of flavonoids delivery consisting of Pluronic P123 and F127 nanomicelles could effectively distribute the drug into tumour tissues, which makes these nanocarriers ideal candidates for passive targeting of cancer cells by the enhanced permeation and retention (EPR) effect. The in vitro cytotoxicity of proposed flavonoids in the Pluronic formulations was investigated by the SRB assay with human colon cancer cells. We designed mixed polymeric micelles, which was a successful drug delivery system for the case of naringenin not being able to enhance the bioavailability and cytotoxic activity of xanthohumol and isoxanthohumol. Furthermore, it was observed that the higher amount of polymer in the formulation achieved better cytotoxic activity.

Astaxanthin (ASX) is a potent lipophilic antioxidant derived from the natural pigment that gives marine animals their distinctive red-orange colour and confers protection from ultraviolet radiation. Self nano-emulsifying drug delivery systems (SNEDDS) have been successfully developed and evaluated to increase the skin penetration of ASX and target its antioxidant and anti-inflammatory potential to the epidermis and dermis. SNEDDS were prepared using a low-temperature spontaneous emulsification method, and their physical characteristics, stability, antioxidant activity, and skin penetration were characterized. Terpenes (D-limonene, geraniol, and farnesol) were included in the SNEDDS formulations to evaluate their potential skin penetration enhancement. An HPLC assay was developed that allowed ASX recovery from skin tissues and quantification. All SNEDDS formulations had droplets in the 20 nm range, with low polydispersity. ASX stability over 28 days storage in light and dark conditions was improved and antioxidant activity was high. SNEDDS-L1 (no terpene) gave significantly increased ASX penetration to the stratum corneum (SC) and the epidermis-dermis-follicle region (E + D + F) compared to an ASX in oil solution and a commercial ASX facial serum product. The SNEDDS-containing D-limonene gave the highest ASX permeation enhancement, with 3.34- and 3.79-fold the amount in the SC and E + D + F, respectively, compared to a similar applied dose of ASX in oil. We concluded that SNEDDS provide an effective formulation strategy for enhanced skin penetration of a highly lipophilic molecule, and when applied to ASX, have the potential to provide topical formulations for UV protection, anti-aging, and inflammatory conditions of the skin.

Poor water solubility and low bioavailability of active pharmaceutical ingredients (APIs) are major causes of friction in the pharmaceutical industry and represent a formidable hurdle for pharmaceutical drug development. Drug delivery remains the major challenge for the application of new small-molecule drugs as well as biopharmaceuticals. The three challenges for synthetic delivery systems are: (i) controlling drug distribution and clearance in the blood; (ii) solubilizing poorly water-soluble agents, and (iii) selectively targeting specific tissues. Although several polymer-based systems have addressed the first two demands and have been translated into clinical practice, no targeted synthetic drug delivery system has reached the market. This Review is designed to provide a background on the challenges and requirements for the design and translation of new polymer-based delivery systems. This report will focus on chemical approaches to drug delivery for systemic applications.