Advanced Technologies for Drug Delivery, Pathogen Detection and Diagnostics

Technegas was developed in Australia as an imaging radioaerosol in the late 1980s and is now commercialized by Cyclomedica, Pty Ltd. for diagnosing pulmonary embolism (PE). Technegas is produced by heating technetium-99m in a carbon crucible for a few seconds at high temperatures (2750 °C) to generate technetium–carbon nanoparticles with a gas-like behaviour. The submicron particulates formed allow easy diffusion to the lung periphery when inhaled. Technegas has been used for diagnosis in over 4.4 m patients across 60 countries and now offers exciting opportunities in areas outside of PE, including asthma and chronic obstructive pulmonary disease (COPD). The Technegas generation process and the physicochemical attributes of the aerosol have been studied over the past 30 years in parallel with the advancement in different analytical methodologies. Thus, it is now well established that the Technegas aerosol has a radioactivity aerodynamic diameter of <500 nm and is composed of agglomerated nanoparticles. With a plethora of literature studying different aspects of Technegas, this review focuses on a historical evaluation of the different methodologies’ findings over the years that provides insight into a scientific consensus of this technology. Also, we briefly discuss recent clinical innovations using Technegas and a brief history of Technegas patents. Full article

Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide, affecting over 10 million people annually, with an estimated cost of $76.5 billion. Although apocynin freely transverses the blood–brain barrier (BBB), its application is limited due to its rapid elimination, low terminal half-life (t1/2 = 6.7 min), narrow dose–response relationship, and cytotoxicity, thereby requiring repeated dosages. With this study, we aimed to develop transferrin-functionalized nanoparticles encapsulating apocynin to treat neuroinflammation for targeted drug delivery to sites of brain injury. As a preliminary approach, we endeavored to optimize the formulation parameters of apocynin-loaded albumin nanoparticles prepared through the desolvation method. The nanoparticles were characterized for their size, polydispersity, surface charge, drug loading and in vitro drug release. In this study, we also investigated the anti-inflammatory and neuroprotective effects of free apocynin and nanoparticle-loaded apocynin in neuronal cells. We show that the developed formulation displayed monodispersed, nanosized particles with higher entrapment efficiency, loading, stability, and sustained release profiles. The permeability of the nanoparticles across HBMECs reached the maximum at 67%. The in vivo evaluation revealed the enhanced uptake of transferrin-anchored nanoparticles in the brain tissues when compared with unmodified nanoparticles after I.V. administration. In vivo nanoparticle localization studies using a blast TBI (bTBI) model and confocal fluorescence microscopy have shown that tf-apoANPs are successful in delivering relatively high amounts of nanoparticles to the brain parenchyma and glial cells compared to non-targeted nanoparticles. We also establish that targeted nanoparticles accumulate in the brain. In conclusion, tf-apoANPs are efficacious carriers for targeted delivery across the blood–brain barrier to potentially treat neuroinflammation in brain injury and other diseases. Full article

The aim of this study was to explore the proof of concept for using Raman spectroscopy as a diagnostic platform in the setting of systemic lupus erythematosus (SLE). We sought to identify unique Raman signatures in serum blood samples to successfully segregate SLE patients from healthy controls (HC). In addition, a retrospective audit was undertaken to assess the clinical utility of current testing platforms used to detect anti-double stranded DNA (dsDNA) antibodies (n = 600). We examined 234 Raman spectra to investigate key variances between SLE patients (n = 8) and HC (n = 4). Multi-variant analysis and classification model construction was achieved using principal component analysis (PCA), PCA-linear discriminant analysis and partial least squares-discriminant analysis (PLS-DA). We achieved the successful segregation of Raman spectra from SLE patients and healthy controls (p-value < 0.0001). Classification models built using PLS-DA demonstrated outstanding performance characteristics with 99% accuracy, 100% sensitivity and 99% specificity. Twelve statistically significant (p-value < 0.001) wavenumbers were identified as potential diagnostic spectral markers. Molecular assignments related to proteins and DNA demonstrated significant Raman intensity changes between SLE and HC groups. These wavenumbers may serve as future biomarkers and offer further insight into the pathogenesis of SLE. Our audit confirmed previously reported inconsistencies between two key methodologies used to detect anti-dsDNA, highlighting the need for improved laboratory testing for SLE. Raman spectroscopy has demonstrated powerful performance characteristics in this proof-of-concept study, setting the foundations for future translation into the clinical setting. Full article

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide, causing progressive cognitive decline, memory impairment, and neurological deficits. Methylene blue (MB), an antioxidant, has emerged as a potential drug for the treatment of AD owing to its cognitive improvement and neuroprotective functions. Despite the small molecular size of MB, which can cross the BBB, the therapeutic effective dosage using a BBB-permeable delivery system in a specific brain localization remains unclear. In this study, we presented magnetic resonance–guided focused ultrasound (MRgFUS) as a delivery system to enhance BBB permeability for the effective treatment of AD. MRgFUS using two ultrasound intensities (0.25 and 0.32 MPa) was used to intravenously deliver MB to the hippocampal region. Compared with treatment with 0.25 MPa FUS, treatment with 0.32 MPa FUS significantly enhanced MB brain accumulation. Deposition of amyloid-β (Aβ) plaques and neural cell damage was significantly reduced in 0.32 MPa FUS/MB-treated APP/PS1 mice. Furthermore, aquaporin-4 expression increased significantly in the 0.32 MPa FUS and 0.32 MPa FUS/MB groups without glial fibrillary acidic protein activation. The results from this study demonstrate that FUS improved MB delivery to the brain, and FUS/MB combination treatment reduced the number of Aβ plaques. This study revealed the potential of FUS-BBBD as an effective strategy to enhance the efficacy of therapeutic drugs for AD. Full article

The skin harbors a huge number of different microorganisms such as bacteria, fungi and viruses, and it acts as a protective shield to prevent the invasion of pathogens and to maintain the health of the commensal microbiota. Several studies, in fact, have shown the importance of the skin microbiota for healthy skin. However, this balance can be altered by intrinsic and extrinsic factors, leading to the development of skin disease, such as acne vulgaris (AV), atopic dermatitis (AD) and rosacea(RS). Although these diseases are widespread and affect both adolescents and adults, the scientific correlation between these disorders and the skin microbiota and physiological parameters (TEWL, hydration and lipid composition) is still unclear. This review aims to investigate the current literature regarding the correlation between the skin microbiota and its imbalance underlying microbiological aspects, how the skin microbiota changes over the course of the disease and the current possible treatments. The following reported studies show a general imbalance of the bacterial flora. For this reason, more in-depth studies are necessary to explore the different subspecies and strains involved in all three diseases. Full article

Despite a considerable number of new antibiotics under going clinical trials, treatment of intracellular pathogens still represents a major pharmaceutical challenge. The use of lipid nanocarriers provides several advantages such as protection from compound degradation, increased bioavailability, and controlled and targeted drug release. Wheat germ agglutinin (WGA) is known to have its receptors on the alveolar epithelium and increase phagocytosis. The present study aimed to produce nanostructured lipid carriers with novel glycosylated amphiphilic employed to attach WGA on the surface of the nanocarriers to improve intracellular drug delivery. High-pressure homogenization was employed to prepare the lipid nanocarriers. In vitro, high-content analysis and flow cytometry assay was employed to study the increased uptake by macrophages when the nanocarriers were grafted with WGA. A lipid nanocarrier with surface-functionalized WGA protein (~200 nm, PDI > 0.3) was successfully produced and characterized. The system was loaded with a lipophilic model compound (quercetin; QU), demonstrating the ability to encapsulate a high amount of compound and release it in a controlled manner. The nanocarrier surface functionalization with the WGA protein increased the phagocytosis by macrophages. The system proposed here has characteristics to be further explored to treat intracellular pathogens. Full article

Traditional adhesives or glues such as cyanoacrylates, fibrin glue, polyethylene glycol, and their derivatives have been widely used in biomedical fields. However, they still suffer from numerous limitations, including the mechanical mismatch with biological tissues, weak adhesion on wet surfaces, biological incompatibility, and incapability of integrating desired multifunction. In addition to adaptive mechanical and adhesion properties, adhesive biomaterials should be able to integrate multiple functions such as stimuli-responsiveness, control-releasing of small or macromolecular therapeutic molecules, hosting of various cells, and programmable degradation to fulfill the requirements in the specific biological systems. Therefore, rational molecular engineering and structural designs are required to facilitate the development of functional adhesive materials. This review summarizes and analyzes the current supramolecular design strategies of representative adhesive materials, serving as a general guide for researchers seeking to develop novel adhesive materials for biomedical applications. Full article

Tuberculosis (TB) remains one of the leading causes of death worldwide and is caused by the single infectious agent Mycobacterium tuberculosis (Mtb). Although sputum is the most common specimen for pulmonary TB detection, some other respiratory specimens, such as bronchoalveolar lavage (BAL) fluid, gastric lavage (GL), and induced sputum (IS), are also collected from patients who are unable to deliver sputum. In this study, we aimed to evaluate the diagnostic performances of different test methods for TB diagnosis using BAL fluid specimens from sputum-scarce pulmonary TB patients. In this current study, a total of 210 BAL fluid specimens were collected and subjected to culture on Lowenstein–Jensen (L-J) medium, using an N-acetyl-L-cysteine-Sodium Hydroxide decontamination and digestion method, Xpert MTB/RIF (Xpert, Cepheid, Sunnyvale, CA, USA) assay, and acid-fast bacilli (AFB) microscopy with a Ziehl–Neelsen staining method for the detection of pulmonary TB. The sensitivity and specificity of these methods were then analyzed against the composite reference standard (CRS). Additionally, the receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of these assays. Among the 210 specimens, 39 (18.6%), 27 (12.8%), and 12 (5.7%) were found positive with Xpert assay, culture, and AFB microscopy, respectively. Considering the CRS, 42 (20%) were positive as the final diagnosis. The Xpert assay had a significantly higher sensitivity (92.9%, 95% CI: 80.5–98.5) compared to culture (64.3%, 95% CI: 48.0–78.4) and AFB microscopy (28.6%, 95% CI: 15.7–44.6) against the CRS. Additionally, the area under the ROC curve (AUC) for the Xpert assay, culture, and AFB microscopy accounted for 0.964, 0.821, and 0.655, respectively, when using CRS as the reference. In conclusion, our study findings demonstrated that the Xpert assay conferred a considerable diagnostic potential compared to other conventional methods for the diagnosis of pulmonary TB from BAL fluid specimens. Full article