Search

Preclinical, clinical and epidemiologic studies have established the potent anticancer and radiosensitisation effects of HMG-CoA reductase inhibitors (statins). However, the low bioavailability of oral statin formulations is a key barrier to achieving effective doses within tumour. To address this issue and ascertain the radiosensitisation potential of simvastatin, we developed a parenteral high density lipoprotein nanoparticle (HDL NP) formulation of this commonly used statin. A scalable method for the preparation of the simvastatin-HDL NPs was developed using a 3D printed microfluidic mixer. This enables the production of litre scale amounts of particles with minimal batch to batch variation. Simvastatin-HDL NPs enhanced the radiobiological response in 2D/3D head and neck squamous cell carcinoma (HNSCC) in vitro models. The simvastatin-HDL NPs radiosensitisation was comparable to that of 10 and 5 times higher doses of free drug in 2D and 3D cultures, respectively, which could be partially explained by more efficient cellular uptake of the statin in the nanoformulation as well as by the inherent biological activity of the HDL NPs on the cholesterol pathway. The radiosensitising potency of the simvastatin-HDL nanoformulation was validated in an immunocompetent MOC-1 HNSCC tumour bearing mouse model. This data supports the rationale of repurposing statins through reformulation within HDL NPs. Statins are safe and readily available molecules including as generic, and their use as radiosensitisers could lead to much needed effective and affordable approaches to improve treatment of solid tumours. Refereed/Peer-reviewed

Continued advances in label-free electrical biosensors pave the way to simple, rapid, cost-effective, high-sensitivity, and quantitative biomarker testing at the point-of-care setting that would profoundly transform healthcare. However, implementation in routine diagnostics is faced with significant challenges associated with the inherent requirement for biofluid sample processing before and during testing. We present here a simple yet robust autonomous finger-prick blood sample processing platform integrated with nanoscale field-effect transistor biosensors and demonstrate the feasibility of measuring the SARS-CoV-2 nucleocapsid protein. The 3D-printed platform incorporates a high-yield blood-to-plasma separation module and a delay valve designed to terminate the assay at a specific time. The platform is driven by hydrostatic pressure to efficiently and automatically dispense plasma and washing/measurement buffer to the nanosensors. Our model study demonstrates the feasibility of detecting down to 1.4 pg/mL of the SARS-CoV-2 nucleocapsid protein within 25 min and with only minimal operator intervention. Refereed/Peer-reviewed

Intratumoral administration of immune checkpoint inhibitors, such as programmed cell death-1 antibodies (aPD-1), is a promising approach toward addressing both the low patients' responses and high off-target toxicity, but good preclinical results have not translated in phase I clinical studies as significant off-target toxicities were observed. We hypothesized that the nanoformulation of aPD-1 could alter both their loco-regional and systemic distribution following intratumoral administration. To test this hypothesis, we developed an aPD-1 nanoformulation (aPD-1 NPs) and investigated its biodistribution following intratumoral injection in an orthotopic mice model of head and neck cancer. Biodistribution analysis demonstrated a significantly lower distribution in off-target organs of the nanoformulated aPD-1 compared to free antibodies. On the other hand, both aPD-1 NPs and free aPD-1 yielded a significantly higher tumor and tumor draining lymph node accumulation than the systemically administrated free aPD-1 used as the current clinical benchmark. In a set of comprehensive in vitro biological studies, aPD-1 NPs effectively inhibited PD-1 expression on T-cells to a similar extent to free aPD-1 and efficiently potentiated the cytotoxicity of T-cells against head and neck cancer cells in vitro. Further studies are warranted to assess the potential of this intratumoral administration of aPD-1 nanoformulation in alleviating the toxicity and enhancing the tumor efficacy of immune checkpoint inhibitors. Refereed/Peer-reviewed

Microfluidic organs‐on‐chips are rapidly being developed toward eliminating the shortcomings of static in vitro models and better addressing basic and translational research questions. A critical aspect is the dynamic culture environment they provide. However, the associated inherent requirement for controlled fluid shear stress (FSS) and therefore the need for precise pumps limits their implementation. To address this issue, here a novel approach to manufacture pumpless and tubeless organs‐on‐chips is reported. It relies on the use of a hydrophilic thread to provide a driving force for the perfusion of the cell culture medium through constant evaporation in the controlled conditions of a cell incubator. Well‐defined and tuneable flow rates can be applied by adjusting the length and/or diameter of the thread. This approach for the preparation of an intestine‐on‐chip model based on the Caco‐2 cell line is validated. Five days culture under 0.02 dyn·cm−2 shear conditions yield monolayers similar to those prepared using a high‐precision peristaltic pump. A pumpless device can also be used to delineate the effect of FSS on the phenotype of adenocarcinomic human alveolar basal epithelial A549 cells. It is anticipated that the pumpless approach will facilitate and herefore increase the use of organs‐on‐chips models in the future. Refereed/Peer-reviewed