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  • From ‘fixed dose combinations’ to ‘a dynamic dose combiner’: 3D printed bi-layer antihypertensive tablets

    Sadia, M.; Isreb, Abdullah; Abbadi, I.; Isreb, Mohammad; Aziz, D.; Selo, A.; Timmins, P.; Alhnan, M.A. (2018-10)
    There is an increased evidence for treating hypertension by a combination of two or more drugs. Increasing the number of daily intake of tablets has been reported to negatively affect the compliance of patients. Therefore, numerous fixed dose combinations (FDCs) have been introduced to the market. However, the inherent rigid nature of FDCs does not allow the titration of the dose of each single component for an individual patient's needs. In this work, flexible dose combinations of two anti-hypertensive drugs in a single bilayer tablet with a range of doses were fabricated using dual fused deposition modelling (FDM) 3D printer. Enalapril maleate (EM) and hydrochlorothiazide (HCT) loaded filaments were produced via hot-melt extrusion (HME). Computer software was utilised to design sets of oval bi-layer tablets of individualised doses. Thermal analysis and x-ray diffractometer (XRD) indicated that HCT remained crystalline in the polymeric matrix whilst EM appeared to be in an amorphous form. The interaction between anionic EM and cationic methacrylate polymer may have contributed to a drop in the glass transition temperature (Tg) of the filament and obviated the need for a plasticiser. Across all tablet sets, the methacrylate polymeric matrix provided immediate drug release profiles. This dynamic dosing system maintained the advantages of FDCs while providing a superior flexibility of dosing range, hence offering an optimal clinical solution to hypertension therapy in a patient-centric healthcare service.
  • Bacterial diversity in Buruli ulcer skin lesions: Challenges in the clinical microbiome analysis of a skin disease

    Van Leuvenhaege, C.; Vandelannoote, K.; Affolabi, D.; Portaels, F.; Sopoh, G.; de Jong, B.C.; Eddyani, M.; Meehan, Conor J. (2017-07-27)
    Background Buruli ulcer (BU) is an infectious disease caused by Mycobacterium ulcerans and considered the third most prevalent mycobacterial disease in humans. Secondary bacterial infections in open BU lesions are the main cause of pain, delayed healing and systemic illness, resulting in prolonged hospital stay. Thus, understanding the diversity of bacteria, termed the microbiome, in these open lesions is important for proper treatment. However, adequately studying the human microbiome in a clinical setting can prove difficult when investigating a neglected tropical skin disease due to its rarity and the setting. Methodology/Principal findings Using 16S rRNA sequencing, we determined the microbial composition of 5 BU lesions, 3 non-BU lesions and 3 healthy skin samples. Although no significant differences in diversity were found between BU and non-BU lesions, the former were characterized by an increase of Bacteroidetes compared to the non-BU wounds and the BU lesions also contained significantly more obligate anaerobes. With this molecular-based study, we were also able to detect bacteria that were missed by culture-based methods in previous BU studies. Conclusions/Significance Our study suggests that BU may lead to changes in the skin bacterial community within the lesions. However, in order to determine if such changes hold true across all BU cases and are either a cause or consequence of a specific wound environment, further microbiome studies are necessary. Such skin microbiome analysis requires large sample sizes and lesions from the same body site in many patients, both of which can be difficult for a rare disease. Our study proposes a pipeline for such studies and highlights several drawbacks that must be considered if microbiome analysis is to be utilized for neglected tropical diseases.
  • First archaeobotanical plant macro-remain analysis from the Middle Bronze Age wetland settlement of Viverone (Viverone “Emissario” Project: campaign Viv16)

    Herbig, C.; Jennings, Benjamin R. (2019)
    The first archaeobotanical studies of the Middle Bronze Age lakeshore settlement demonstrate the enormous potential of this site for appropriate analyses. On the basis of the well-preserved layers a multitude of plant remains and wide diversity of species are present at this site. Evidence of emmer, spelt, tetraploid naked wheat, hulled barley, peas and broad beans conforms to the basic cultural crop spectrum of the Middle Bronze Age. The wild plants originate from various locations in the direct vicinity and allow an insight into the landscape at that time. Numerous wild plants were intentionally used by the settlers. Fruits gathered include cornelian cherries, hazelnuts, crab apples and a diversity of berries. Furthermore, archaeobotanical analyses support observations already made on site that within the settlement there are at least two functionally different areas. While in section 50/51 the layers contain the remains of daily food preparation, section 7 indicates a link to animal fodder.
  • Multi method investigation of submerged features at Semblister, Shetland

    Christie, C.; Stratigos, M.; Jennings, Benjamin R. (2019)
    The Shetland Islands are well known for their archaeology, with many features from later prehistory surviving to an exceptional degree, with brochs being an excellent example. Less is known of submerged prehistoric sites, though the offshore profile of the islands means that ancient occupation of the current submerged zone was likely, and also that the sites are likely preserved. One such archaeological site, previously identified, occurs near Semblister. The site has been known locally, and is recorded as a broch in the local Historic Environment Records, however, its dimensions and location do not strongly suggest that it is a broch. Combining satellite imagery – the site is in relatively shallow water and visible – with targeted side-scan sonar survey and data processing, will aid the development of a process approach to the re-classification / confirmation of historically recorded sites, and archaeological prospection in the shallow water zone.
  • Structure reactivity relationship in the accelerated formation of 2,3-diarylquinoxalines in the microdroplets of a nebuliser

    Hayat, Nadia; Fenwick, Nathan W.; Saidykhan, Amie; Telford, Richard; Martin, William H.C.; Gallagher, R.T.; Bowen, Richard D. (2019)
    Competition experiments in which 1,2-phenylenediamine, C6H4(NH2)2, condenses with equimolar quantities of benzil, (C6H5CO)2, and a 3,3'- or 4,4'-disubstituted benzil (XC6H4CO)2 (X = F, Cl, Br, CH3 or CH3O) to form a mixture of 2,3-diphenylquinoxaline and the corresponding 2,3-diarylquinoxaline (Ar = XC6H4) in the microdroplets produced in a nebuliser allow a Hammett relationship with a ρ value of 1.85 to be developed for this accelerated condensation in the nebuliser. This structure reactivity relationship reveals that an appreciable amount of negative charge builds up on the carbon of the carbonyl group of the benzil during the rate-limiting step of the reaction, thus confirming that this process involves nucleophilic addition of the 1,2-phenylenediamine to the benzil. In general, the presence of an electron donating substituent, particularly in the 4 and 4' positions, in the benzil retards the reaction, whereas an electron attracting substituent, especially in the 3 and 3' position, accelerates it.
  • Vibrational spectroscopic characterisation of salmeterol xinafoate polymorphs and a preliminary investigation of their transformation using simultaneous in situ portable Raman spectroscopy and differential scanning calorimetry

    Ali, H.R.H.; Edwards, Howell G.M.; Hargreaves, Michael D.; Munshi, Tasnim; Scowen, Ian J.; Telford, Richard (2008-07)
    Knowledge and control of the polymorphic phases of chemical compounds are important aspects of drug development in the pharmaceutical industry. Salmeterol xinafoate, a long acting β-adrenergic receptor agonist, exists in two polymorphic Forms, I and II. Raman and near infrared spectra were obtained of these polymorphs at selected wavelengths in the range of 488–1064 nm; significant differences in the Raman and near-infrared spectra were apparent and key spectral marker bands have been identified for the vibrational spectro-scopic characterisation of the individual polymorphs which were also characterised with X ray diffractometry. The solid-state transition of salmeterol xinafoate polymorphs was studied using simultaneous in situ portable Raman spectroscopy and differential scanning calorimetry isothermally between transitions. This method assisted in the unambiguous characterisation of the two polymorphic forms by providing a simultaneous probe of both the thermal and vibrational data. The study demonstrates the value of a rapid in situ analysis of a drug polymorph which can be of potential value for at-line in-process control.
  • Critical characteristics for corticosteroid solution metered dose inhaler bioequivalence

    Grainger, C.I.; Saunders, M.; Buttini, F.; Telford, Richard; Merolla, L.L.; Martin, G.P.; Jones, S.A.; Forbes, B. (2012-03)
    Determining bioequivalence for solution pressurized metered dose inhalers (pMDI) is difficult because the critical characteristics of such products are poorly defined. The aim of this study was to elucidate the non-aerodynamic properties of the emitted aerosol particles from two solution pMDI products that determine their biopharmaceutical differences after deposition. Novel particle capture and analysis techniques were employed to characterize the physicochemical and biopharmaceutical properties of two beclomethasone dipropionate (BDP) products: QVAR and Sanasthmax. The BDP particles emitted from the Sanasthmax inhaler were discernibly different those emitted from QVAR in terms of size (50% larger, less porous), solid state (less crystalline) and dissolution (20-fold slower). When deposited onto the surface of respiratory epithelial cell layers, QVAR delivered ∼50% more BDP across the cell layer in 60 min than Sanasthmax. Biopharmaceutical performance was not attributable to individual particle properties as these were manifold with summative and/or competing effects. The cell culture dissolution− absorption model revealed the net effect of the particle formed on drug disposition and was predictive of human systemic absorption of BDP delivered by the test inhalers. This illustrates the potential of the technique to detect the effect of formulation on the performance of aerosolized particles and contribute to assessment of bioequivalence.
  • 3D Printing of a Multi-Layered Polypill Containing Six Drugs Using a Novel Stereolithographic Method

    Robles-Martinez, P.; Xu, X.; Trenfield, S.J.; Awad, A.; Goyanes, A.; Telford, Richard; Basit, A.W.; Gaisford, S. (2019-06)
    Three-dimensional printing (3DP) has demonstrated great potential for multi-material fabrication because of its capability for printing bespoke and spatially separated material conformations. Such a concept could revolutionise the pharmaceutical industry, enabling the production of personalised, multi-layered drug products on demand. Here, we developed a novel stereolithographic (SLA) 3D printing method that, for the first time, can be used to fabricate multi-layer constructs (polypills) with variable drug content and/or shape. Using this technique, six drugs, including paracetamol, cffeine, naproxen, chloramphenicol, prednisolone and aspirin, were printed with dfferent geometries and material compositions. Drug distribution was visualised using Raman microscopy, which showed that whilst separate layers were successfully printed, several of the drugs diffused across the layers depending on their amorphous or crystalline phase. The printed constructs demonstrated excellent physical properties and the different material inclusions enabled distinct drug release profiles of the six actives within dissolution tests. For the first time, this paper demonstrates the feasibility of SLA printing as an innovative platform for multi-drug therapy production, facilitating a new era of personalised polypills.
  • Apolipoprotein E ε4 allele modulates the immediate impact of acute exercise on prefrontal function

    De Marco, M.; Clough, P.J.; Dyer, C.E.; Vince, R.V.; Waby, Jennifer S.; Midgley, A.W.; Venneri, A. (2015-01)
    The difference between Apolipoprotein E ε4 carriers and non-carriers in response to single exercise sessions was tested. Stroop and Posner tasks were administered to young untrained women immediately after walking sessions or moderately heavy exercise. Exercise had a significantly more profound impact on the Stroop effect than on the Posner effect, suggesting selective involvement of prefrontal function. A significant genotype-by-exercise interaction indicated differences in response to exercise between ε4 carriers and non-carriers. Carriers showed facilitation triggered by exercise. The transient executive down-regulation was construed as due to exercise-dependent hypofrontality. The facilitation observed in carriers was interpreted as better management of prefrontal metabolic resources, and explained within the antagonistic pleiotropy hypothesis framework. The findings have implications for the interpretation of differences between ε4 carriers and non-carriers in the benefits triggered by long-term exercise that might depend, at least partially, on mechanisms of metabolic response to physical activity.
  • An alternative synthesis of Vandetanib (CaprelsaTM) via a microwave accelerated Dimroth rearrangement

    Brocklesby, K.L.; Waby, Jennifer S.; Cawthorne, C.; Smith, G. (2017-04-12)
    Vandetanib is an orally available tyrosine kinase inhibitor used in the treatment of cancer. The current synthesis proceeds via an unstable 4-chloroquinazoline, using harsh reagents, in addition to requiring sequential protection and deprotection steps. In the present work, use of the Dimroth rearrangement in the key quinazoline forming step enabled the synthesis of Vandetanib in nine steps (compared to the previously reported 12–14).
  • Levels of state and trait anxiety in patients referred to ophthalmology by primary care clinicians: a cross sectional study

    Davey, Christopher J.; Harley, C.; Elliott, David B. (2013-06-13)
    Purpose There is a high level of over-referral from primary eye care leading to significant numbers of people without ocular pathology (false positives) being referred to secondary eye care. The present study used a psychometric instrument to determine whether there is a psychological burden on patients due to referral to secondary eye care, and used Rasch analysis to convert the data from an ordinal to an interval scale. Design Cross sectional study. Participants and Controls 322 participants and 80 control participants. Methods State (i.e. current) and trait (i.e. propensity to) anxiety were measured in a group of patients referred to a hospital eye department in the UK and in a control group who have had a sight test but were not referred. Response category analysis plus infit and outfit Rasch statistics and person separation indices were used to determine the usefulness of individual items and the response categories. Principal components analysis was used to determine dimensionality. Main Outcome Measure Levels of state and trait anxiety measured using the State-Trait Anxiety Inventory. Results State anxiety scores were significantly higher in the patients referred to secondary eye care than the controls (p<0.04), but similar for trait anxiety (p>0.1). Rasch analysis highlighted that the questionnaire results needed to be split into “anxiety-absent” and “anxiety-present” items for both state and trait anxiety, but both subscales showed the same profile of results between patients and controls. Conclusions State anxiety was shown to be higher in patients referred to secondary eye care than the controls, and at similar levels to people with moderate to high perceived susceptibility to breast cancer. This suggests that referral from primary to secondary eye care can result in a significant psychological burden on some patients.
  • Geographical inequalities in uptake of NHS funded eye examinations: Poisson modelling of small-area data for Essex, UK

    Shickle, D.; Farragher, T.M.; Davey, Christopher J.; Slade, S.V.; Syrett, J. (2018-06)
    Background: Small-area analysis of National Health Service (NHS)-funded sight test uptake in Leeds showed significant inequalities in access among people aged <16 or ≥60. Methods: Data were extracted from 604 126 valid General Ophthalmic Services (GOS)1 claim forms for eye examinations for Essex residents between October 2013 and July 2015. Expected GOS1 uptake for each lower super output area was based on England annual uptake. Poisson regression modelling explored associations in GOS1 uptake ratio with deprivation. Results: People aged ≥60 or <16 living in the least deprived quintile were 15% and 26%, respectively, more likely to have an NHS funded eye examination than the most deprived quintile, although all are equally entitled. GOS1 uptake is higher in the more deprived quintiles among 16-59-year old, as means tested social benefits are the main eligibility criteria in this age-group. Inequalities were also observed at local authority level. Conclusions: Inequalities in access among people ≥60 years were not as large as those reported in Leeds, although inequalities in <16-year old were similar. However, demonstrable inequalities in this data set over a longer time period and a larger and more diverse area than Leeds, reinforce the argument that interventions are needed to address eye examination uptake inequalities.
  • A needs assessment for a minor eye condition service within Leeds, Bradford and Airedale, UK

    Swystun, Alexander G.; Davey, Christopher J. (2019-08)
    Background: There are a number of limitations to the present primary eye care system in the UK. Patients with minor eye conditions typically either have to present to their local hospital or GP, or face a charge when visiting eye care professionals (optometrists). Some areas of the UK have commissioned enhanced community services to alleviate this problem; however, many areas have not. The present study is a needs assessment of three areas (Leeds, Airedale and Bradford) without a Minor Eye Conditions Service (MECS), with the aim of determining whether such a service is clinically or economically viable. Method: A pro forma was developed for optometrists and practice staff to complete when a patient presented whose reason for attending was due to symptoms indicative of a problem that could not be optically corrected. This form captured the reason for visit, whether the patient was seen, the consultation funding, the outcome and where the patient would have presented to if the optometrists could not have seen them. Optometrists were invited to participate via Local Optical Committees. Results were submitted via a Google form or a Microsoft Excel document and were analysed in Microsoft Excel. Results: Seventy-five percent of patients were managed in optometric practice. Nine and 16% of patients required subsequent referral to their General Practitioner or hospital ophthalmology department, respectively. Should they not have been seen, 34% of patients would have presented to accident and emergency departments and 59% to their general practitioner. 53% of patients paid privately for the optometrist appointment, 28% of patients received a free examination either through use of General Ophthalmic Service sight tests (9%) or optometrist good will (19%) and 19% of patients did not receive a consultation and were redirected to other providers (e.g. pharmacy, accident and emergency or General Practitioner). 88% of patients were satisfied with the level of service. Cost-analyses revealed a theoretical cost saving of £3198 to the NHS across our sample for the study period, indicating cost effectiveness. Conclusions: This assessment demonstrates that a minor eye condition service in the local areas would be economically and clinically viable and well received by patients.
  • Anticancer, antifungal and antibacterial potential of bis(β-ketoiminato)ruthenium(II) carbonyl complexes

    Madzivire, C.R.; Carames-Mendez, P.; Pask, C.M.; Phillips, Roger M.; Lord, Rianne M.; McGowan, P.C. (2019-12-01)
    Herein we report a library of new ruthenium(II) complexes which incorporate a range of functionalised β -ketoiminate ligands. The complexes undergo an unusual reduction from Ru(III) to Ru(II), and consequently incorporate carbonyl ligands from the 2-ethoxyethanol solvent, forming ruthenium dicarbonyl complexes. In order to address the potential applications of these complexes, we have screened the library against a range of tumour cell lines, however, all compounds exhibit low cellular activity and this is tentatively assigned to the decomposition of the compounds in aqueous media. Studies to establish the antifungal and antibacterial potential of these complexes was addressed and show increased growth inhibitions for C. neoformans and S. aureus species.
  • Essential and Checkpoint Functions of Budding Yeast ATM and ATR during Meiotic Prophase Are Facilitated by Differential Phosphorylation of a Meiotic Adaptor Protein, Hop1

    Penedos, A.; Johnson, A.L.; Strong, E.; Goldman, Alastair S.H.; Carballo, J.A.; Cha, R.S. (2015-07-30)
    A hallmark of the conserved ATM/ATR signalling is its ability to mediate a wide range of functions utilizing only a limited number of adaptors and effector kinases. During meiosis, Tel1 and Mec1, the budding yeast ATM and ATR, respectively, rely on a meiotic adaptor protein Hop1, a 53BP1/Rad9 functional analog, and its associated kinase Mek1, a CHK2/Rad53-paralog, to mediate multiple functions: control of the formation and repair of programmed meiotic DNA double strand breaks, enforcement of inter-homolog bias, regulation of meiotic progression, and implementation of checkpoint responses. Here, we present evidence that the multi-functionality of the Tel1/Mec1-to-Hop1/Mek1 signalling depends on stepwise activation of Mek1 that is mediated by Tel1/Mec1 phosphorylation of two specific residues within Hop1: phosphorylation at the threonine 318 (T318) ensures the transient basal level Mek1 activation required for viable spore formation during unperturbed meiosis. Phosphorylation at the serine 298 (S298) promotes stable Hop1-Mek1 interaction on chromosomes following the initial phospho-T318 mediated Mek1 recruitment. In the absence of Dmc1, the phospho-S298 also promotes Mek1 hyper-activation necessary for implementing meiotic checkpoint arrest. Taking these observations together, we propose that the Hop1 phospho-T318 and phospho-S298 constitute key components of the Tel1/Mec1- based meiotic recombination surveillance (MRS) network and facilitate effective coupling of meiotic recombination and progression during both unperturbed and challenged meiosis.
  • Correction: Essential and Checkpoint Functions of Budding Yeast ATM and ATR during Meiotic Prophase Are Facilitated by Differential Phosphorylation of a Meiotic Adaptor Protein, Hop1

    Penedos, A.; Johnson, A.L.; Strong, E.; Goldman, Alastair S.H.; Carballo, J.A.; Cha, R.S. (2016-04-18)
    In the section “Generation of phospho-specific Hop1 antibodies” of the Materials and Methods, we made several mistakes when indicating the sequence of the peptides used for the generation of antibodies.
  • A set of novel CRISPR-based integrative vectors for Saccharomyces cerevisiae.

    Daniels, P.W.; Mukherjee, A.; Goldman, Alastair S.H.; Hu, B. (2018)
    Integrating a desired DNA sequence into the yeast genomes is a widely-used genetic manipulation in the budding yeast Saccharomyces cerevisiae. The conventional integration method is to use an integrative plasmid such as pRS or YIplac series as the target DNA carrier. The nature of this method risks multiple integrations of the target DNA and the potential loss of integrated DNA during cell proliferation. In this study, we developed a novel yeast integration strategy based on the widely used CRISPR-Cas9 system and created a set of plasmids for this purpose. In this system, a plasmid bearing Cas9 and gRNA expression cassettes will induce a double-strand break (DSB) inside a biosynthesis gene such as Met15 or Lys2. Repair of the DSB will be mediated by another plasmid bearing upstream and downstream sequences of the DSB and an integration sequence in between. As a result of this repair the sequence is integrated into genome by replacing the biosynthesis gene, the disruption of which leads to a new auxotrophic genotype. The newly-generated auxotroph can serve as a traceable marker for the integration. In this study, we demonstrated that a DNA fragment up to 6.3 kb can be efficiently integrated into the Met15 or Lys2 locus using this system. This novel integration strategy can be applied to various yeasts, including natural yeast isolated from wild environments or different yeast species such as Candida albicans.
  • Local chromosome context is a major determinant of crossover pathway biochemistry during budding yeast meiosis

    Medhi, D.; Goldman, Alastair S.H.; Lichten, M. (2016-11-18)
    Abstract The budding yeast genome contains regions where meiotic recombination initiates more frequently than in others. This pattern parallels enrichment for the meiotic chromosome axis proteins Hop1 and Red1. These proteins are important for Spo11-catalyzed double strand break formation; their contribution to crossover recombination remains undefined. Using the sequence-specific VMA1-derived endonuclease (VDE) to initiate recombination in meiosis, we show that chromosome structure influences the choice of proteins that resolve recombination intermediates to form crossovers. At a Hop1-enriched locus, most VDE-initiated crossovers, like most Spo11-initiated crossovers, required the meiosis-specific MutLγ resolvase. In contrast, at a locus with lower Hop1 occupancy, most VDE-initiated crossovers were MutLγ-independent. In pch2 mutants, the two loci displayed similar Hop1 occupancy levels, and VDE-induced crossovers were similarly MutLγ-dependent. We suggest that meiotic and mitotic recombination pathways coexist within meiotic cells, and that features of meiotic chromosome structure determine whether one or the other predominates in different regions.
  • Specific gyrA gene mutations predict poor treatment outcome in MDR-TB

    Rigouts, L.; Coeck, N.; Gumusboga, M.; de Rijk, W.B.; Aung, K.J.; Hossain, M.A.; Fissette, K.; Rieder, H.L.; Meehan, Conor J.; de Jong, B.C.; et al. (2016-02)
    Mutations in the gyrase genes cause fluoroquinolone resistance in Mycobacterium tuberculosis. However, the predictive value of these markers for clinical outcomes in patients with MDR-TB is unknown to date. The objective of this study was to determine molecular markers and breakpoints predicting second-line treatment outcomes in M. tuberculosis patients treated with fourth-generation fluoroquinolones. We analysed treatment outcome data in relation to the gyrA and gyrB sequences and MICs of ofloxacin, gatifloxacin and moxifloxacin for pretreatment M. tuberculosis isolates from 181 MDR-TB patients in Bangladesh whose isolates were susceptible to injectable drugs. The gyrA 90Val, 94Gly and 94Ala mutations were most frequent, with the highest resistance levels for 94Gly mutants. Increased pretreatment resistance levels (>2 mg/L), related to specific mutations, were associated with lower cure percentages, with no cure in patients whose isolates were resistant to gatifloxacin at 4 mg/L. Any gyrA 94 mutation, except 94Ala, predicted a significantly lower proportion of cure compared with all other gyrA mutations taken together (all non-94 mutants + 94Ala) [OR = 4.3 (95% CI 1.4-13.0)]. The difference in treatment outcome was not explained by resistance to the other drugs. Our study suggests that gyrA mutations at position 94, other than Ala, predict high-level resistance to gatifloxacin and moxifloxacin, as well as poor treatment outcome, in MDR-TB patients in whom an injectable agent is still effective.
  • Theranostic nanoparticles enhance the response of glioblastomas to radiation

    Wu, W.; Klockow, J.L.; Mohanty, S.; Ku, K.S.; Aghighi, M.; Melemenidis, S.; Chen, Z.; Li, K.; Ribeiro Morais, Goreti; Zhao, N.; et al. (ivyspring, 2019-09-17)
    Despite considerable progress with our understanding of glioblastoma multiforme (GBM) and the precise delivery of radiotherapy, the prognosis for GBM patients is still unfavorable with tumor recurrence due to radioresistance being a major concern. We recently developed a cross-linked iron oxide nanoparticle conjugated to azademethylcolchicine (CLIO-ICT) to target and eradicate a subpopulation of quiescent cells, glioblastoma initiating cells (GICs), which could be a reason for radioresistance and tumor relapse. The purpose of our study was to investigate if CLIO-ICT has an additive therapeutic effect to enhance the response of GBMs to ionizing radiation. Methods: NSG™ mice bearing human GBMs and C57BL/6J mice bearing murine GBMs received CLIO-ICT, radiation, or combination treatment. The mice underwent pre- and post-treatment magnetic resonance imaging (MRI) scans, bioluminescence imaging (BLI), and histological analysis. Tumor nanoparticle enhancement, tumor flux, microvessel density, GIC, and apoptosis markers were compared between different groups using a one-way ANOVA and two-tailed Mann-Whitney test. Additional NSG™ mice underwent survival analyses with Kaplan–Meier curves and a log rank (Mantel–Cox) test. Results: At 2 weeks post-treatment, BLI and MRI scans revealed significant reduction in tumor size for CLIO-ICT plus radiation treated tumors compared to monotherapy or vehicle-treated tumors. Combining CLIO-ICT with radiation therapy significantly decreased microvessel density, decreased GICs, increased caspase-3 expression, and prolonged the survival of GBM-bearing mice. CLIO-ICT delivery to GBM could be monitored with MRI. and was not significantly different before and after radiation. There was no significant caspase-3 expression in normal brain at therapeutic doses of CLIO-ICT administered. Conclusion: Our data shows additive anti-tumor effects of CLIO-ICT nanoparticles in combination with radiotherapy. The combination therapy proposed here could potentially be a clinically translatable strategy for treating GBMs.

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