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Illustration of the fluorescent ratio probe (OPDEA/BOD-NO2) with hypoxia targeting and hypoxia activation capacity for in vivo tumour imaging.

Despite the enormous advancements in nanomedicine research, a limited number of nanoformulations are available on the market, and few have been translated to clinics. An easily scalable, sustainable, and cost-effective manufacturing strategy and long-term stability for storage are crucial for successful translation. Here, we report a system and method to instantly formulate NF achieved with a nanoscale polyelectrolyte coacervate-like system, consisting of anionic pseudopeptide poly(l-lysine isophthalamide) derivatives, polyethylenimine, and doxorubicin (Dox) via simple "mix-and-go" addition of precursor solutions in seconds. The coacervate-like nanosystem shows enhanced intracellular delivery of Dox to patient-derived multidrug-resistant (MDR) cells in 3D tumor spheroids. The results demonstrate the feasibility of an instant drug formulation using a coacervate-like nanosystem. We envisage that this technique can be widely utilized in the nanomedicine field to bypass the special requirement of large-scale production and elongated shelf life of nanomaterials.

A rapid and comprehensive assessment of ischemic stroke (IS) is critical for clinicians to take the most appropriate treatment. Currently, IS assessment is mainly carried out by computed tomography (CT) and magnetic resonance imaging (MRI) in combination with observing the clinical symptoms and inquiring about contraindications. However, they cannot diagnose pathological conditions and judge the microenvironment in real-time. Near-infrared (NIR) fluorescence imaging has advantages for IS imaging, such as high sensitivity, high spatiotemporal resolution, and straightforward real-time operation. Herein, a pH-responsive fluorescent liposomal probe (BOD@Lip) was prepared for in vivo real-time visualization of the degree of IS based on the different acid microenvironments in the progression of the disease. The fluorescence imaging with BOD@Lip showed the degree of IS, and the correlation between fluorescence signals and the neurological deficit scores was established for the first time. This work provided a new method to objectively evaluate the degree of IS through a visualized route and a new insight into the relationship between the acidic microenvironment and the progression of IS. This article is protected by copyright. All rights reserved.

Tumor-selective drug delivery could enhance anticancer efficacy and avoid drug side effects. However, because of tumor heterogeneity, current nanoparticle-based drug delivery systems rarely improve clinical outcomes significantly, commonly only reducing systemic toxicity. In this work, a new tumor-specific, tyrosinase-responsive cascade amplification release nanoparticle (TR-CARN) was developed to fulfill the needs for tumor-specific drug delivery and high efficacy cancer treatment. Tyrosinase (Tyr) is specifically expressed in melanomas and can catalyze acetaminophen (APAP) to increase reactive oxygen species (ROS). It was therefore utilized here to initiate the ROS amplification procedure. In TR-CARN, a ROS-responsive prodrug BDOX was loaded into an amphiphilic polymer, and APAP was linked to the polymer through a ROS-cleavable thioether bond. TR-CARN caused reduced side effects during the delivery because of the low toxicity of BDOX. Once TR-CARN entered into the tumor, endogenous ROS triggered initial APAP and BDOX release. Tyr-mediated ROS synthesis by APAP then accelerated APAP and BDOX release and toxification. Consequently, TR-CARN achieved melanoma-specific treatment of high efficacy through the cascade amplification strategy with enhanced biosafety.

Funder: University of Cambridge WD Armstrong Trust, Funder: University of Cambridge Kurt Hahn Trust, Funder: Studienstiftung des Deutschen Volkes; funder-id: http://dx.doi.org/10.13039/501100004350, BACKGROUND: Breastfeeding is critical to health outcomes, particularly in low-resource settings where there is little access to clean water. For infants in their first twelve months of life, the delivery of medications is challenging, and use of oral syringes to deliver liquid formulations can pose both practical and emotional challenges. OBJECTIVE: To explore the potential to deliver medicine to infants via a solid formulation during breastfeeding. METHODS: Single center feasibility study within a tertiary level neonatal unit in the UK, involving twenty-six breastfeeding mother-infant dyads. A solid formulation of Vitamin B12 was delivered to infants during breastfeeding. Outcomes included the quantitative change in serum vitamin B12 and assessment of maternal expectations and experiences. RESULTS: Delivery of Vitamin B12 through a solid formulation that dissolved in human milk did not impair breastfeeding, and Vitamin B12 levels rose in all infants from a mean baseline (range) 533 pg/mL (236-925 pg/mL) to 1871 pg/mL (610-4981 pg/mL) at 6-8 hours post-delivery. Mothers described the surprising ease of 'drug' delivery, with 85% reporting a preference over the use of syringes. CONCLUSIONS: Solid drug formulations can be delivered during breastfeeding and were preferred by mothers over the delivery of liquid formulations via a syringe.

Spinal cord injury (SCI) is one of the most debilitating injuries, and transplantation of stem cells in a scaffold is a promising strategy for treatment. However, stem cell treatment of SCI has been severely impaired by the increased generation of reactive oxygen species in the lesion microenvironment, which can lead to a high level of stem cell death and dysfunction. Herein, a MnO

Cornea diseases are a leading cause of blindness and the disease burden is exacerbated by the increasing shortage around the world for cadaveric donor corneas. Despite the advances in the field of regenerative medicine, successful transplantation of laboratory made artificial corneas has not been fully realised in clinical practice. The causes of failure of such artificial corneal implants are multifactorial and include latent infections from viruses and other micorbes, enzyme over-expression, implant degradation, extrusion or delayed epithelial regeneration. Therefore, there is an urgent unmet need for developing customized corneal implants to suit the host environment, counter the effects of inflammation or infection and that are able to track early signs of implant failurein situ. In the present work, we describe a nano toolbox comprising tools for drug release and in addition capable of being infection responsive, promoting regeneration including non-invasive monitoring ofin situcorneal environment. These nano constructs can be incorporated within pro-regenerative biosynthetic implants, transforming them into theranostic devices able to respond to biological changes following implantation.

Glycerol and trehalose are widely used protective agents in the cryopreservation of red blood cells (RBCs). This chapter presents a protocol for use of these agents as cryoprotectants of RBCs, with post-thaw assessment of cell survival and cellular oxidative-reductive status. The main aim is to provide a framework for further studies aimed at improving RBC survival and function and to supply improved biomaterials for studies on RBC biochemistry, major operations, as well as those for urgent use in emergency room situations.

The current trend in industrial biotechnology is to move from batch or fed‐batch fermentations to continuous operations. The success of this transition will require the development of genetically stable production strains, the use of strong constitutive promoters, and the development of new medium formulations that allow an appropriate balance between cell growth and product formation. We identified genes that showed high expression in Komagataella phaffii during different steady‐state conditions and explored the utility of promoters of these genes (Chr1–4_0586 and FragB_0052) in optimizing the expression of two different r‐proteins, human lysozyme (HuLy), and the anti‐idiotypic antibody fragment, Fab‐3H6, in comparison with the widely used glyceraldehyde‐3‐phosphate dehydrogenase promoter. Our results showed that the promoter strength was highly dependent on the cultivation conditions and thus constructs should be tested under a range of conditions to determine both the best performing clone and the ideal promoter for the expression of the protein of interest. An important benefit of continuous production is that it facilitates the use of the genome‐scale metabolic models in the design of strains and cultivation media. In silico flux distributions showed that production of either protein increased the flux through aromatic amino acid biosynthesis. Tyrosine supplementation increased the productivity for both proteins, whereas tryptophan addition did not cause any significant change and, phenylalanine addition increased the expression of HuLy but decreased that of Fab‐3H6. These results showed that a genome‐scale metabolic model can be used to assess the metabolic burden imposed by the synthesis of a specific r‐protein and then this information can be used to tailor a cultivation medium to increase production.

An in vitro simulation system was developed to study the effect of an infant's peristaltic tongue motion during breastfeeding on oral rapidly disintegrating tablets in the mouth, for use in rapid product candidate screening. These tablets are being designed for use inside a modified nipple shield worn by a mother during breastfeeding, a proposed novel platform technology to administer drugs and nutrients to breastfeeding infants. In this study, the release of a model compound, sulforhodamine B, from tablet formulations was studied under physiologically relevant forces induced by compression and rotation of a tongue mimic. The release profiles of the sulforhodamine B in flowing deionized water were found to be statistically different using 2-way ANOVA with matching, when tongue mimic rotation was introduced for 2 compression levels representing 2 tongue strengths (p = 0.0013 and p < 0.0001 for the lower and higher compression settings, respectively). Compression level was found to be a significant factor for increasing model compound release at rotational rates representing nonnutritive breastfeeding (p = 0.0162). This novel apparatus is the first to simulate the motion and pressures applied by the tongue and could be used in future infant oral product development.

With the cell therapy industry continuing to grow, the ability to preserve clinical grade cells, including mesenchymal stem cells (MSCs), whilst retaining cell viability and function remains critical for the generation of off-the-shelf therapies. Cryopreservation of MSCs, using slow freezing, is an established process at lab scale. However, the cytotoxicity of cryoprotectants, like Me

Amphipathic pH-responsive polymers have shown to increase the permeability of cell membranes to trehalose hence improving the cryopreservation of mammalian cells. However, the trafficking of both the polymer and trehalose across the cell membrane has not yet been thoroughly analysed. The objective of this study was to investigate the effect on cryopreservation of the trafficking of the disaccharide trehalose along PP-50, an amphipathic polymer, through an osteosarcoma cell line (SAOS-2). Confocal microscopy analysis confirmed the presence of intracellular labelled trehalose only when incubated in the presence of PP-50. Further analysis confirmed that both trehalose and PP-50 localised in the cytoplasm, accumulated mainly in the perinuclear area. Quantitative analysis of the colocalisation between trehalose and PP-50 showed Pearson and Manders coefficients of 0.862 ± 0.008 and 0.766 ± 0.033, respectively, suggesting a high degree of intracellular colocalisation between these molecules. Cryopreserved cells pre-incubated with trehalose and PP-50 showed increased cryosurvival when compared with cells pre-incubated in the absence of the polymer. PP-50 showed to be directly involved in the uptake of trehalose, a critical characteristic towards use in cryopreservation and biomedical applications.

We report the encapsulation of the hydrophilic model molecule calcein in the Zr-based MOF UiO-66, followed by amorphization of the framework by ball-milling. We show controlled release of calcein over more than 30 days, compared with the 2 day release period from crystalline UiO-66.

A micro-capillary film has been developed that offers the potential for an at-line analytical tool for rapid aggregate analysis during biopharmaceutical antibody production. A non-porous walled micro-capillary film (NMCF) with cation exchange functionality was demonstrated to act as a chromatography medium that could be operated with high linear fluid velocities and was highly resistant to blockage by entrained particulates, including cells. The NMCF containing 19 parallel microcapillaries was prepared using a melt extrusion process from poly(ethylene-vinyl alcohol) copolymer (EVOH). The NMCF-EVOH was modified to have cation-exchange functionality (NMCF-EVOH-SP) and shown to differentially bind monomer and aggregated species of IgG antibody directly from a bioreactor. The use of NMCF-EVOH-SP to quantify aggregate concentrations in monoclonal antibody preparations in less than 20 minutes was demonstrated.