Magnetosomes and Magnetosome Mimics: Preparation, Cancer Cell Uptake and Functionalization for Future Cancer Therapies.

Magnetic magnetite nanoparticles (MNP) are heralded as model vehicles for nanomedicine, particularly cancer therapeutics. However, there are many methods of synthesizing different sized and coated MNP, which may affect their performance as nanomedicines. Magnetosomes are naturally occurring, lipid-coated MNP that exhibit exceptional hyperthermic heating, but their properties, cancer cell uptake and toxicity have yet to be compared to other MNP. Magnetosomes can be mimicked by coating MNP in either amphiphilic oleic acid or silica. In this study, magnetosomes are directly compared to control MNP, biomimetic oleic acid and silica coated MNP of varying sizes. MNP are characterized and compared with respect to size, magnetism, and surface properties. Small (8 ± 1.6 nm) and larger (32 ± 9.9 nm) MNP are produced by two different methods and coated with either silica or oleic acid, increasing the size and the size dispersity of the MNP. The coated larger MNP are comparable in size (49 ± 12.5 nm and 61 ± 18.2 nm) to magnetosomes (46 ± 11.8 nm) making good magnetosome mimics. All MNP are assessed and compared for cancer cell uptake in MDA-MB-231 cells and importantly, all are readily taken up with minimal toxic effect. Silica coated MNP show the most uptake with greater than 60% cell uptake at the highest concentration, and magnetosomes showing the least with less than 40% at the highest concentration, while size does not have a significant effect on uptake. Finally, surface functionalization is demonstrated for magnetosomes and silica coated MNP using biotinylation and EDC-NHS, respectively, to conjugate fluorescent probes. The modified particles are visualized in MDA-MB-231 cells and demonstrate how both naturally biosynthesized magnetosomes and biomimetic silica coated MNP can be functionalized and readily up taken by cancer cells for realization as nanomedical vehicles

220th ENMC workshop: Dystroglycan and the dystroglycanopathies Naarden, The Netherlands, 27–29 May 2016

Highlights • Review of clinical phenotypes associated with the dystroglycanopathies. • Discussion of current animal models and their contribution to understanding the disease process. • New insight into the glycosylation of alpha dystroglycan and the role of LARGE. • Structural information on the LARGE glycan

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

The development of a novel magnetic nanomedicine for the treatment of aggressive metastatic breast cancer

Background: Oncolytic virotherapy is a novel immunotherapy generating success in clinical studies in multiple cancer types. However, clinical use of oncolytic viruses (OVs) to date is limited to superficial tumours due to poor tumour penetration and viral elimination by the immune system following systemic delivery. A way to overcome this, is to use magnetic nanoparticles (MNPs) in combination with magnetic drug targeting. This customisability of MNPs allows for the stable conjugation of OVs and the controlled drug release of additional drug molecules. The aim of this PhD was to develop a magnetic nanomedicine (MNM) consisting of the OV (Herpes Simplex Virus1716 (HSV1716)) and a chemotherapy (epirubicin), bound to MNPs. We hypothesise that this will improve drug delivery into aggressive breast cancer (BC) cells using an external magnetic field. Methods: The intrinsic physical and chemical characteristics of the MNM were determined prior to pre-clinical analysis using XRD, FRIT, TEM, SQUID (as well as others). The oncolytic and pro-inflammatory potential of the MNM was investigated in vitro in a panel of BC cell lines using plaque assays, alamar blue and RT-PCR. The tolerability and antitumour efficacy of the MNM was assessed using pre-clinical models of primary and metastatic BC. Results: MNPs were successfully functionalised and biochemically conjugate to a pH sensitive epirubicin and HSV1716 resulting in a stable complex, even after freeze-thawing. Moreover, the MNM was as cytotoxic as the individual drugs in murine and human BC cell lines, and could potentially generate a pro-inflammatory response. All animals tolerated the MNM treatment regime with no adverse effects in both primary and metastatic models, with the MNM demonstrating the ability to cross the blood brain barrier following systemic delivery. Moreover, therapeutic efficacy was observed through reduced tumour burden and prolonged survival. Conclusion: In summary, we have developed a novel MNM which is effective in pre-clinical models of BC. Future studies will further seek to address the antitumour activity of the MNM, as well as its bio-distribution following treatment in vivo. Future consideration will need to be given to the MNM for production and scale up for clinical use.