{"title":"Abstract","authors":"","doi":"10.1002/jin2.14","DOIUrl":null,"url":null,"abstract":"<p>Shahd Abuhelal (<span>[email protected]</span>)*</p><p><i>King's College London/Institute of Pharmaceutical Science</i></p><p>siRNA treatment can result in decreased protein expression and could be used to treat cancer or other diseases. Successful application depends on efficient delivery inside target cells. Here, we aim to design and optimise a nano-carrier suitable for siRNA delivery, with high encapsulation efficiency and stability for use in vitro and in vivo to target cancer.</p><p>Liposomes and pH-sensitive peptides assembled as ternary complex were investigated as siRNA delivery systems. Physicochemical characteristics (size, zeta potential, siRNA maintenance, release and aggregation) were tested. Cell uptake and luciferase knock down were evaluated in vitro, and some complexes tested for biodistribution <i>in vivo</i>.</p><p>Hydrodynamic size and zeta potential of the lipoplex, peptide complexes and ternary complexs were similar. Although lipoplexes showed better encapsulation, they were less stable in serum. Ternary complexes offered better protection for the siRNA. Improved cell uptake was seen for ternary complexes in comparison with peptide complex and lipoplex. Knock down studies revealed optimal effects ternary complexes, and preliminary <i>in vivo</i> experiments showed tumour accumulation of lipoplex.</p><p>These siRNA delivery vehicles appear promising for in vivo applications, and work is now focused on the improvement of cell targeting, in vitro and in vivo PK/PD.</p><p>Chris Adams (<span>[email protected]</span>)*</p><p><i>Keele University</i></p><p>Magnetic nanoparticles (MNPs) are key translational platforms with the ability to label cells for non-invasive imaging and genetically engineer cells for release of therapeutic biomolecules. We show for the first time that application of magnetic fields can safely enhance MNP mediated labelling and genetic engineering of autologous canine olfactory mucosal cells (cOMCs), a key veterinary cell population for treatment of spinal injury in companion dogs. Crucially, the developed protocols were successfully combined with advanced minicircle DNA vectors to deliver brain derived neurotrophic factor (important in promoting nerve fibre outgrowth) to cOMCs. Minicircles have distinct advantages for clinical gene delivery due to their small size, lack of bacterial backbone and duration of transgene expression. Finally, we also show that MNP labelling can facilitate imaging of cOMCs encapsulated in implantable collagen hydrogels using non-invasive magnetic resonance imaging. A combination of these methodologies could enable translation of safe and effective cOMC transplantation strategies.</p><p>Mohammad Ahmad Abdallah Al-Natour (<span>[email protected]</span>)*</p><p><i>University and Institution: University of Nottingham</i></p><p><b>Abstract</b></p><p>Recent years have witnessed unexpected growth of research on the medical applications of nanotechnology (nanomedicine), especially the use of nanoparticles (NPs) in the diagnosis and treatment of disease. Among these polymeric NPs have many advantages; they can be prepared from biocompatible FDA approved polymers, easily functionalized with smart ligands, and tailored to control the release of encapsulated drugs. However the impact of these NPs at the molecular and cellular levels has not been fully studied.</p><p>We have applied cell based metabolomics methodology to investigate the cellular metabolic changes in human-like macrophages after exposure to five different poly(lactic-co-glycolic acid (PLGA) NPs. The study revealed that all NPs induced oxidative stress and shift in energy metabolism from citric acid cycle to glycolysis. However none of them were toxic. Metabolites fold changes showed that PEG-PLGA NPs had the minor impact on the cellular metabolism.</p><p>Wejdan Al-Shakarchi (<span>[email protected]</span>)*</p><p><i>Institute for Science and Technology in Medicine, Keele University</i></p><p><b>Abstract</b></p><p>Hepatocellular carcinoma accounts for 85% of liver cancers that originate in liver cells. This type of tumour is characterised by defective or ineffective apoptosis, which is considered to be the main cause of cancer progression. Cytochrome-C (heme protein) triggers mitochondrial apoptosis and is responsible for activation of the downstream caspase apoptosis pathway during cell death in tumour cells. However, there is a significant difficulty in the delivery of proteins through the cell membrane. Iron-gold hybrid nanoparticles (HNP-C) application offers a promising tool for cytochrome-c delivery into tumour cells and enhances the specific targeting of therapeutic particles to their site of action.</p><p>Anticancer drugs (doxorubicin, paclitaxel, oxaliplatin, vinblastine and vincristine) with different mechanisms of action were used to treat the HepG2 cells at specific concentrations to assess their IC50 values, and subsequently the cells were treated with each one of these drugs in combination with HNP-Cytochrome C showing a 10% growth inhibition alone in HepG2 cells.</p><p>The successful delivery of pro-apoptotic protein (cytochrome-C) using hybrid iron-oxide gold nanoparticles can be considered as a promising step in the liver cancer treatment by working in synergism pattern with anticancer drugs and significant decrease in the IC50 of each drugs combination against the HepG2 cells viability.</p><p>Ali Alazzo (<span>[email protected]</span>)*</p><p><i>University of Nottingham/School of Pharmacy</i></p><p>Non-viral gene delivery systems have been investigated for many years; however, the successful clinical translation of this approach is still limited due to several biological and technical obstacles that should be overcome to prepare a successful vector. Highly branched and easily functionalized polymers have emerged as an attractive solution to address these barriers. In this context, hyperbranched polymers represent a promising alternative to dendrimers for their advantages in terms of cost that make synthesis more feasible and applicable for scale up and manufacturing. Here, we investigated the effect of histidine on the structure and gene delivery applications of thermally polymerized hyperbranched polylysine. The structural analysis indicated that the incorporation of histidine modulates the structure of hyperbranched polylysine to produce a more dendritic polymer with less flexible branches. Additionally, the results revealed that there was a negative correlation between the content of histidine in the polymers and their capability to condense and deliver nucleic acid.</p><p>Mohanad Alfahad (<span>[email protected]</span>)*</p><p><i>Institute of Science and Technology in Medicine (ISTM), Keele University</i></p><p>Pancreatic cancer is the fourth main cancer in the western world. Gemcitabine treatment only proves effective in 23.8% of patients with pancreatic cancer. Nanotechnology can play an essential role by delivering anticancer drugs to the malignant cells in a targeted fashion,</p><p>In this part of the study, we have investigated the Prodrug attachment to hybrid nanoparticle surface via dative covalent linkage.</p><p>The HNP were synthesized, coated with PEI and gold. Prodrug of Gemcitabine was synthesized using established procedures.</p><p>Attachment of prodrugs on to HNP surface was quantified using reverse phase HPLC. In vitro drug release studies were carried out at different temperatures.</p><p>Novel prodrugs of gemcitabine were isolated and characterized. HNPs were synthesized successfully in the magnitude of 70 nm. Prodrug attachment to HNP was successful with as much as 5 mg mL-1 being detected. Drug release studies indicated that the formulation was stable over the range of temperatures tested.</p><p>Ali Alsuraifi (<span>[email protected]</span>)*</p><p><i>Institute for Science and Technology in Medicine, Keele University, Keele ST5 5BG, UK</i></p><p><b>Abstract</b></p><p>A limitation associated with cancer treatment arises from the problems in directing highly cytotoxic agents to the diseased tissues, low solubility in aqueous media and poor bioavailability. Many drug delivery systems have been devised to address this problem, including thermoresponsive polymers. In this study, a novel HPMA-CO-AMPA-R thermoresponsive copolymer has been prepared to act as drug delivery system and to enhance the solubility of poor water-soluble drugs via grafted hydrophobic groups onto the primary amine group of APMA monomers using palmitoyl, dansyl, cholesteryl and 5-(4-chlorophenyl)-1,3,4- oxadiazole. The product characterization was carried out by FTIR, NMR and Zeta Sizer. Drug loading and release abilities of HPMA-CO-AMPA-R copolymers were determined by using HPLC.</p><p>Aurelien Trichet (<span>[email protected]</span>)*</p><p><i>University of Oxford, Department of Materials</i></p><p>Within the last decade, optical resonators, thanks to their low mode volume and/or high finesse, have emerged as a promising avenue to isolate and measure real-time properties of single nanoparticles such as viruses or gold nanoparticles. Such trapping devices with sensing capabilities are on the verge of finding powerful applications in interdisciplinary science. However, the quest for a candidate bringing together in-situ detection, trapping and multiple quantitative measurements of the particle properties supported by a comprehensive understanding still remain elusive.</p><p>Patrick Ball (<span>[email protected]</span>)*</p><p><i>Bangor University</i></p><p>Directed enzyme prodrug therapy (DEPT) is a form of cancer chemotherapy that involves the delivery of prodrug-activating enzymes to a tumour before administering a prodrug to the patient, resulting in a higher local toxicity than current chemotherapy strategies. The bacterial nitroreductase NfnB has been investigated for potential use in DEPT in combination wuth the CB1954 prodrug and this combination has even reached the clinical trial stage. A mojor limitation of this technology is the dose limiting toxicity of the CB1954 prodrug and as such other produgs need to be explored for use in DEPT strategies. The two novel mustard prodrugs, PR-104A and SN27686, developed at Auckland University, New Zealand, are the most promising prodrugs available and as such are currently being tested in combination with the NfnB enzyme using the novel gold-coated magnetic nanoparticle delivery system developed at Bangor University, Wales.</p><p>Mike Burgum (<span>[email protected]</span>)*</p><p><i>Swansea University</i></p><p>Few-layer graphene (FLG), defined as possessing three or more atomic layers of graphene, is a revolutionary material stronger than diamond and more conductive than copper. The present study sought to assess the toxicological impact of 700 m<sup>2</sup>/g FLG flakes engineered with (i) no specific functionality, (ii) amine groups or (iii) carboxyl groups. Each FLG was then exposed to a representative human airway epithelial monoculture of 16HBE14o<sup>-</sup> cells.</p><p>Size and morphology of the flakes were characterised with scanning electron microscopy (SEM) and atomic force microscopy (AFM). Cell viability and chromosomal damage were assessed by relative population doubling (RPD) and the cytokinesis block micronucleus (CBMN) assay respectively.</p><p>FLG induced no significant cytotoxicity at any of the tested concentrations. In contrast, at sub-lethal concentrations, significant genotoxicity was induced by both non- and amine-functionalised FLG from 20 µg/ml whilst the carboxyl-functionalised flakes induced a significant response at 100 µg/ml.</p><p>Jake Casson (<span>[email protected]</span>)*</p><p><i>University of Glasgow</i></p><p>Skeletal metastasis is prevalent in many cancers, in particular epithelial tumours (eg. breast cancer). It is now evident that, in the early stages of metastatic spread, disseminated tumour cells in the bone marrow undergo an extended period of growth arrest in response to the microenvironment, a phenomenon known as dormancy. Understanding the mechanism of transition from dormancy to a recurrent growth state is limited by the availability of physiologically relevant models. In this project we have developed a co-culture model to explore this transition, utilising 3D cell spheroids of both breast cancer cells and bone marrow mesenchymal stromal cells, co-cultured over a monolayer of intact or scratch wounded fibroblasts. The release of interleukin-6 (IL-6) has been documented when performing a scratch assay on fibroblasts. Our findings indicate the presence of IL-6 causes breast cancer cells to migrate out of the spheroid, indicating a switch from dormancy to an active growth state.</p><p>Dr Oliver Castell (<span>[email protected]</span>)*</p><p><i>Cardiff University - College of Biomedical and Life Science, School of Pharmacy and Pharmaceutical Sciences</i></p><p>Droplet Interface Bilayers (DIBs) represent artificial mimics of the cell membrane suitable for biophysical studies and applications in synthetic biology. Self-assembly of lipid at a droplet water-oil interface creates a lipid monolayer, and the contacting of two such interfaces forms a bilayer. Functional membrane proteins can be reconstituted into these bilayers. Total Internal Reflection Fluorescence (TIRF) microscopy can be used to make dynamic single molecule measurements, allowing the unpicking of intrinsic molecular mechanisms of the membrane, with a level of insight not afforded by traditional ensemble techniques. Here we highlight the use of droplet interface bilayers to make optical measurements of protein function and to make single molecule measurements on the dynamics of membrane organisation. Such measurements in well controlled model systems serve to increase our understanding of the membrane at the molecular level, providing unique insight into the nanoscale mechanisms underpinning complex cellular functions.</p><p>Dr Helen Cauldbeck (<span>[email protected]</span>)*</p><p><i>University of Liverpool, Department of Chemistry</i></p><p>Complicated cases of retinal detachment are treated with silicone oil (SiO) tamponades which can potentially be used as drug reservoirs. Various methodologies to develop a sustained and controlled drug release, for a clinically-relevant release period, 6-8 weeks, from SiO tamponades were investigated. The solubility and release of drugs from SiO was assessed using radioisotope techniques. The formation of prodrugs and novel polymer architectures with hydrophilic components that show considerable miscibility. Further additive development of SiO may produce enhanced and tailored release profiles. Cytotoxicity of drugs and synthesised additives were studied against an adult retinal pigment epithelium cell line (ARPE-19).</p><p>Natalie Cureton (<span>[email protected]</span>)*</p><p><i>University and Institution: Insitute of Human Development, University of Manchester</i></p><p><b>Abstract</b></p><p>Pregnancy complications are often attributed to poor uteroplacental blood flow, but the risk of systemic side-effects hinders therapeutic intervention. We have used novel peptide-conjugated liposomes that selectively bind to the uteroplacental vasculature to deliver the vasodilator compound SE175 to pregnant endothelial nitric oxide synthase knockout mice, a well-characterised model of fetal growth restriction (FGR).</p><p>Liposomes containing SE175 or PBS were prepared by lipid film hydration and targeting peptides coupled to the liposomal surface. Vehicle control, free SE175, PBS- or SE175-containing liposomes were intravenously injected on embryonic (E) days 11.5, 13.5, 15.5 and 17.5. Animals were sacrificed at E18.5 and fetal and placental weights recorded.</p><p>Targeted delivery of SE175 significantly increased fetal weight compared to vehicle control but no other treatment groups, whilst significantly decreasing placental weight, indicating improved placental efficiency.</p><p>These data suggest that selective delivery of SE175 to the uteroplacental vasculature may represent a novel treatment for FGR.</p><p>Christopher David (<span>[email protected]</span>)*</p><p><i>University of Liverpool, Department of Molecular and Clinical Pharmacology</i></p><p>Polydendrons, a novel nanomaterial, were characterised and subjected to in vitro toxicological and immunological tests. Four polydendrons; comprising two ratios of G2 dendron initiator to PEG, in two sizes, were measured for size and surface charge in various media via dynamic light scattering and zeta potential. Sample sterility, cytotoxicity, ROS generation, glutathione reduction, and influence on autophagy were assessed. Notably the smaller 50:50 polydendron generated 1.35- and 9.64-fold increases in IL-1β and TNFα respectively compared to an untreated control. Also, a 1.53-fold increase in leukocyte proliferation was observed, with no significant effects on plasma coagulation, complement activation, or haemolytic potential.</p><p>Ruiz de Angulo (<span>[email protected]</span>)*</p><p><i>CIC biomaGUNE</i></p><p><b>Abstract</b></p><p>Many pathogens and cancer cells have evolved mechanisms to evade the host immune response, creating an urgent need for developing new, safe and effective vaccine technologies.<sup>[1]</sup> Herein we designed PEGylated magnetite-filled nanoparticles as delivery systems to direct tumour antigens and/or adjuvants to lymph nodes (LNs).</p><p><b>References</b></p><p>[1] D. M. Morens, G. K. Folkers, A. S. Fauci, Nature 2004, 430, 242–9.</p><p>[2] A. Ruiz-de-Angulo, A. Zabaleta, V. Gómez-Vallejo, J. Llop, J. C. Mareque-Rivas, ACS Nano 2016, 10, 1602–18.</p><p>Stephanie Edwards (<span>[email protected]</span>)*</p><p><i>University of Liverpool, Chemistry Department</i></p><p>Amaia Garaikoetxea (<span>[email protected]</span>)*</p><p><i>CIC biomaGUNE</i></p><p>Platinum (II) complexes such as cisplatin are still among the best chemotherapeutic agents for the treatment of a variety of tumours.<sup>1</sup> Their clinical use, however, has important drawbacks (resistance, efficacy etc.) and is dose-limited by systemic toxicity. A new generation of Pt(IV) prodrugs are showing considerable potential for overcoming some of these issues.<sup>2</sup> The use of nanoparticles as nanocarries offers great advantages both to improve the delivery and therapeutic index of these prodrugs and to monitor drug targeting by multimodal imaging.</p><p>References:</p><p>[1] Graf, N.; Lippard, S.J. <i>Adv. Drug Delivery Rev.</i> <b>2012</b>, <i>64</i>, 993-1004.</p><p>[2] Gao, J.; Gu, H.; Xu, B. <i>Acc. Chem. Res.</i> <b>2009</b>, <i>42</i>, 1097-1107.</p><p>[3] Hernández-Gil, J.; Cobaleda-Siles, M.; Zabaleta, A.; Salassa, L.; Calvo, J.; Mareque-Rivas, J.C. <i>Adv. Healthcare Mat.</i> <b>2015</b>, <i>4</i>, 1034-1042.</p><p>Marco Giardiello (<span>[email protected]</span>)*</p><p><i>University of Liverpool/Tandem Nano</i></p><p><b>References</b></p><p>[1] D. M. Morens, G. K. Folkers, A. S. Fauci, <i>Nature</i> <b>2004</b>, <i>430</i>, 242–9.</p><p>[2] A. Ruiz-de-Angulo, A. Zabaleta, V. Gómez-Vallejo, J. Llop, J. C. Mareque-Rivas, <i>ACS Nano</i> <b>2016</b>, <i>10</i>, 1602–18.</p><p>Nina Gómez Blanco (<span>[email protected]</span>)*</p><p><i>CIC biomaGUNE</i></p><p>The main clinical application of iron oxide nanoparticles (IONPs) is as contrast agents for Magnetic Resonance Imaging (MRI). Furthermore, they can be engineered for developing effective theranostic nanosystems that integrate multimodal imaging and cancer therapy.<sup>1</sup> In this context, we are exploring IONPs labelled with <sup>67</sup>Ga in combination with platinum anticancer prodrugs to create a SPECT-MR imaging vehicles which can deliver cisplatin in the reducing environment of tumors. In order to achieve optimal r<sub>2</sub> relaxivity,<sup>2</sup> we prepared IONPs with different shapes and sizes and solubilised them in water by encapsulation within PEG-phospholipids micelles.</p><p><b>References</b></p><p>[1] Hernández-Gil, J.; Cobaleda-Siles, M.; Zabaleta, A.; Salassa, L.; Calvo J.; Mareque-Rivas, J. C.; <i>Adv. Healthcare Mater</i>. <b>2015</b>, 4 (7), 1034-1042.</p><p>[2] Lee N.; Choi Y.; Lee Y.; Park M.; Kyung Moon W.; Hong Choi S.; Hyeon T.; <i>Nano Lett</i>. <b>2012</b>, 12, 3127-3131.</p><p>Faye Hern (<span>[email protected]</span>)*</p><p><i>University of Liverpool</i></p><p>James Hobson (<span>[email protected]</span>)*</p><p><i>University of Liverpool</i></p><p>Oil-in-Water Nanoemulsions loaded with either efavirenz or lopinavir were prepared using homogenisation/solvent evaporation technique to increase the concentration of drug in an aqueous environment. The ability of NEs to permeate intestinal barriers was assessed using Caco-2 transwell system, EFV and LPV loaded NEs were compared with aqueous solutions. NE LPV had significantly increased permeation compared to aqueous LPV, with apparent permeability (Papp) of 6.4 x 10<sup>-5</sup> cm/s vs 2.7 x 10<sup>-6</sup> cm/s (p= <0.05). Comparable results being observed for NE EFV compared to aqueous EFV, with Papp values of 1.1 x 10<sup>-5</sup> cm/s and 8.2 x 10<sup>-6</sup> cm/s respectively (p=<0.05).</p><p>David Howard (<span>[email protected]</span>)*</p><p><i>Swansea University Medical School</i></p><p>Antibody drug conjugates (ADCs) are an emerging class of anti-cancer agents showing great promise in the treatment of advanced cancers. ADCs consist of a tumour-targeting monoclonal antibody conjugated to a cytotoxic payload via blood-stable linkers. These prodrugs bind antigens on the tumour cell surface, are internalised, and upon release of their toxic payloads, induce cell death. Despite the over fifty ADCs currently undergoing clinical trials, only a limited number of different payloads are featured. In light of the challenges inter- and intra-tumour heterogeneity and drug resistance pose to cancer treatment, the expansion of the ADC war chest with payloads operating by diverse mechanisms could prove important in improving ADC efficacies. Herein we describe our efforts to identify and evaluate novel ADC payloads. We report on the anti-tumour effects of a novel ADC payload candidate showing promising efficacy in both type I and II endometrial cancer cell-lines.</p><p>Wei-Hsin Hsu (<span>[email protected]</span>)*</p><p><i>University of Nottingham</i></p><p>In polymeric gene delivery, a biodegradable versatile material with low toxicity has been a predominant criterion. Polyphosphazene is an artificial bioerodible polymer, with potential to generate ample derivatives for pharmaceutical purpose. Herein, we explored the use of a known allylamine-substituted polyphosphazene as a precursor and presented flexible click-chemistry for avoiding unwanted side reactions. We designed a mixed-complex with cationic and anionic polyphosphazenes, not only for stably binding pDNA but also for controlled release of pDNA in endosomal environment. While Mix-plex incubated in the acid environment, the TEM images showed separate phases inside the nanoscale complex, likely indicating pH-induced structural change might facilitate release of pDNA. In transfection of 3D-spheroid of U87MG, Mix-plex can promote gene-transfection into tumour cells, compared with the conventional polyplex. In summary, this polyphosphazene-based nano-complex not only presented functional modification for controlled gene release as well as provided various promising derivatives in gene delivery.</p><p>Dr Yazan S. Khaled (<span>[email protected]</span>)*</p><p><i>University of Leeds, Nanotechnology Group</i></p><p>Abstract:</p><p>Background: There is a need for real-time imaging of colorectal cancer (CRC) to allow tailored surgery. Fluorescent nanoparticles may offer a solution with non-immunoglobulin (non-Ig) targeting molecules possessing advantages over antibodies.</p><p>Aim: We aimed to develop and test fluorescent silica nanoparticles targeted against CRC using an anti-carcinoembryonic antigen (CEA) Adhiron (Ad).</p><p>Methods: Anti-CEA or control Ads were conjugated to silica nanoparticles. Binding of CEA-Ad or control nanoparticles to CRC cells was quantified in vitro using confocal microscopy.</p><p>Results: Dye-doped-(NIR664)-silica nanoparticles were synthesised with a median diameter of ~60 nm. CEA-targeted, SMCC-conjugated nanoparticles, but not control nanoparticles, allowed strong tumour-specific fluorescence when incubated with LoVo (p=0.021), LS174T (p=0.041), and HT29 (p=0.03) respectively. There was no significant difference in fluorescence for CEA-Adhiron vs. CEA-Antibody targeted nanoparticles.</p><p>Conclusion: We are the first to demonstrate specific, in vitro imaging of CRC cells using Adhiron-targeted fluorescent nanoparticles. CEA-Adhiron appears to be a suitable non-Ig targeting molecule.</p><p>Rachita Lahri (<span>[email protected]</span>)*</p><p><i>Institute of Pharmaceutical Science, School of Biomedical Sciences, King's College London</i></p><p>Microwave imaging is a new imaging modality which has attracted a lot of attention recently. Microwave imaging is a technique that exploits the dielectric contrast at microwave frequencies between malignant and the healthy tissues. Microwave – frequency dielectric properties difference between malignant and healthy adipose dominated tissue in the breast is as large as 10:1. However the contrast between malignant and normal glandular/fibro-connective tissue in the breast is no more than 10%. This contrast can be improved by the use of various nanoparticles. Dielectric properties of silicon dioxide, titanium dioxide, zinc oxide and different carbon nanotubes have been measured in water for this study. A significant increase was seen within the dielectric properties when carbon nanotubes were added in water. On the other hand, there was no significant increase seen within the dielectric properties when silicon dioxide, titanium dioxide and zinc oxide were added in water.</p><p>Diana Moreira Leite (<span>[email protected]</span>)*</p><p><i>Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biological Sciences, University of Portsmouth</i></p><p>Brain diseases are responsible for 12% of global deaths and their treatment could benefit from the use of highly potent and specific pharmaceuticals with low inherent toxicity and immunogenicity such as neuropeptides 1. However, for neuropeptide therapies to be realised, peptides need to be able to cross the blood-brain barrier (BBB) and possess enhanced enzymatic stability to ensure adequate brain bioavailability. Lipidisation of peptides has been proven to be a useful strategy to enhance enzymatic stability and BBB permeability, while increasing the amphiphilicity of neuropeptides allows their self-assembly in well-defined nanostructures 2,3. We have developed a neuropeptide amphiphile able to self-assemble and entrap brain impermeable drugs, which; possess enhanced stability to enzymatic degradation, permeates the BBB (all human <i>in vitro</i> BBB model) and targets receptors overexpressed in glioblastoma cells resulting in a novel targeted nanomedicine with a strong anti-proliferative and apoptotic effects <i>in vitro</i>. The proposed nanomedicine can be readily translated and proof of concept in an animal model is under way.</p><p><b>References</b></p><p>[1] Lalatsa, A., et al. Molecular Pharmaceutics 2014, 11, 1081-1093.</p><p>[2] Lalatsa, A., et al. Molecular Pharmaceutics 2012, 9, 1665-1680.</p><p>[3] Lalatsa, A., et al. Journal of Controlled Release 2015, 197, 87-96.</p><p>Martin Levere (<span>[email protected]</span>)*</p><p><i>Department of Chemistry, University of Liverpool</i></p><p>Edyta Lewandowska (<span>[email protected]</span>)*</p><p><i>University of Liverpool, Department of Chemistry, UK</i></p><p>Natasha Lewis (<span>[email protected]</span>)*</p><p><i>University of Glasgow</i></p><p>Wenwei Ma (<span>[email protected]</span>)*</p><p><i>University of Lincoln</i></p><p>Conjugation of biomolecules to nanoparticles can be achieved using well-established chemistries. However, when it comes to structurally complex molecules such as proteins, their diversity makes it difficult to find a unique chemical cross-linking method that consistently produce functional conjugates. Therefore, protocols for immobilisation have to be empirically and tediously optimised case-by-case. Passive adsorption is a straightforward method for decoration of nanoparticles but unfortunately the adsorbed protein is thought to undergo denaturation and may not be uniformly oriented.</p><p>To address this, we are developing intermediate designer proteins that adsorb onto gold nanoparticles and carry a domain which specifically binds to an affinity tag. An arbitrary protein of interest which presents the tag can bind the functionalised particles by simple mixing, with reduced chance to undergo denaturation. Importantly, there is no need for optimisation of the conditions, as these are only determined by the affinity system and not by a nanoparticle-protein interaction.</p><p>Shijoy Mathew (<span>[email protected]</span>)*</p><p><i>University of Glasgow</i></p><p>The human body is complex and prone to deterioration. With advances in medicine and the resultant increased life expectancy, there are several significant age-related conditions involving bone or cartilage deterioration and damage, primarily osteoarthritis and osteoporosis. Regeneration of these tissues via mesenchymal stem cells (MSCs) in the bone marrow is an on-going challenge.</p><p>The use of nanoparticles as a delivery platform in medicine is gaining recognition, due to the benefits conferred by their small size, non-toxicity and multi-valency, which allow for a safer and customizable method of delivery.</p><p>This project aims to use gold nanoparticles to deliver antagomirs (anti-miRNAs) to MSCs, with the aim of manipulating key miRNAs involved in MSC differentiation. MiRNAs are short sequenced RNAs that are involved in the regulation of nearly 30% of the genes in the body. This project aims to exploit their function to promote MSC differentiation into bone or cartilage cells.</p><p>William McDaid (<span>[email protected]</span>)*</p><p><i>Queen's University Belfast, School of Pharmacy</i></p><p>The monoclonal antibody Cetuximab (CTX) has demonstrated limited efficacy in the clinic due to activating mutations which allow cancerous cells to acquire resistance. Due to outstanding success as a targeting agent, this study investigates whether CTX functions better as a targeting agent for drug-loaded nanoparticles (NPs) rather than a monotherapy against CTX-resistant cells. Cancer cells with different K-Ras mutations (known to mediate CTX resistance) were selected and the influence of CTX nanoconjugation was assessed with regards to NP uptake and drug delivery. The chemotherapeutic drug of choice in this study was the topoisomerase I inhibitor, camptothecin (CPT), which induces DNA damage in cancer cells. It was seen that CTX facilitated preferential NP uptake and CPT delivery to cells much more effectively than NPs with no surface modification. This was evident by an elevated level of executioner caspase activation and a higher incidence of apoptosis. These results support the premise that CTX is more competent acting as part of NP conjugate system rather than alone as a monotherapy.</p><p>Ciarán M. Maguire (<span>[email protected]</span>)*</p><p><i>University of Dublin, Trinity College</i></p><p><b>Abstract</b></p><p>The size-dependent optical properties of Quantum Dots (QDs) are frequently exploited for use in medical imaging and labelling applications. Similarly, they elicit profound size-dependent anticoagulant properties, a focus for our research.</p><p><b>References</b></p><p>[1] Graf, N.; Lippard, S. J. <i>Adv. Drug Delivery Rev.</i> <b>2012</b>, <i>64</i>, 993–1004.</p><p>[2] Gao, J.; Gu, H.; Xu, B. <i>Acc. Chem. Res.</i> <b>2009</b>, <i>42</i>, 1097–1107.</p><p>[3] Hernández-Gil, J.; Cobaleda-Siles, M.; Zabaleta, A.; Salassa, L.; Calvo, J.; Mareque-Rivas, J. C. <i>Adv. Healthcare Mat.</i> <b>2015</b>, <i>4</i>, 1034–1042.</p><p>Tahereh Tohidi Moghadam, Assistant Professor (<span>[email protected]</span>; <span>[email protected]</span>)*</p><p><i>Tarbiat Modares University, Tehran, Iran</i></p><p><b>Abstract</b></p><p>David Morse (<span>[email protected]</span>)*</p><p><i>University of Cambridge, Department of Engineering - Nanoscience Centre</i></p><p>Adeolu Oluwasanmi (<span>[email protected]</span>)*</p><p><i>Institute for Science and Technology in Medicine, Keele University</i></p><p><b>Abstract</b></p><p>Pancreatic cancer remains the deadliest form of cancer in terms of its survival rate of only 3.7% after 5 years. To ensure the complete removal of adenocarcinomas of the pancreas, chemotherapy and highly invasive surgery has to be employed which is not possible in many of the elderly patients diagnosed with pancreatic cancer. The treatment of cancer can be multistep but the effects on the patients wellbeing can accumulate until treatment is no longer a viable option.</p><p>Nashwa Mahmoud Osman (<span>[email protected]</span>)*</p><p><i>Liverpool John Moores University, Pharmacy and Biomolecular Sciences</i></p><p>Belen Pan-Castillo (<span>[email protected]</span>)*</p><p><i>Swansea University</i></p><p><b>Abstract</b></p><p>Endometrial cancer is the most common gynaecological malignancy with incidence rates in Wales (25%) higher than in Europe (14%) and North American (16%). Wales presents the worst mortality rate (4.9%) among the UK countries (3.9<b>%).</b> Therefore, new therapeutics are urgently needed to improve survival rates.</p><p>Antibody drug conjugates (ADC) consist of a monoclonal antibody attached to a cytotoxic drug through a linker, having the ability to target and kill cancer cells only, while avoiding the widespread destruction of healthy cells typical of traditional chemotherapy. A novel ADC invented by RBGO academics and codename SNIPER, targets a protein expressed in uterine and ovarian cancers and absent in healthy tissue. Our data indicate SNIPER induces cell death of endometrial cancer cells more effectively than the current ADC in clinical use (Herceptin-ADC). This project aims to explore SNIPER safety and efficacy against gynaecological cancers, as an innovative solution to a current health problem.</p><p>Anil Patel (<span>[email protected]</span>)</p><p><i>University of Glasgow</i></p><p><b>Abstract</b></p><p>Using nanoparticles to induce cancer cell hyperthermia and death is a new and developing technique. Cancer cell vulnerabilities to specific high temperatures (42-45 °C) are exploited through localised heating of Gold nanoparticles (GNPs). These ‘nanoscale heaters’ absorb and convert near infrared (NIR) light into heat via their surface plasmon resonance, thus inducing hypothermia, which in turn induces apoptosis driven cancer cell death.</p><p>In this study, Gold nanoprisms and nanorods were cultured with cancer cell lines, both in 2D monolayer and 3D multicellular tumoroids. Following initial biocompatibility testing, these nanostructures were shown to have no significant effect on cell viability (MTT). SEM and TEM scanning demonstrated clear internalisation of both nanoprisms and rods after 1 hr culture. Utilising a 1 W continuous wave 1064nmNR laser, both monolayer and tumoroid cultures were irradiated, inducing significant cell death monitored via live/dead assay. Subsequent RNA analysis via fluidigm suggested up-regulation of key apoptotic genes, supporting cancer cell apoptosis as a result of hyperthermia induction.</p><p>Simone Pisano (<span>[email protected]</span>)*</p><p><i>Swansea University</i></p><p>Nanoparticles, due to their size and structure, offer the possibility of targeted drug delivery and an innovative and promising approach in the treatment of solid tumour cancers. It is effectively known that free drugs often fail to enter tumour site and exhibit burdensome patient side effects. This project focuses on the fabrication of three nanoparticle formulations (Pluronic F127, PLGA and Chitosan) and their physical and chemical characterization before and after encapsulation of a hydrophobic epidrug, SAHA (a HDAC inhibitor). Epigenetic drugs have been broadly studied on different cancer types. Here we demonstrate epidrug efficacy in an in vitro model of endometrial cancer, the most common gynaecological tumour. Free drug and nanoparticle encapsulated forms are directly comparable, demonstrating an effective encapsulation and therapeutic approach which may be a valid and viable delivery method for future applications in all gynaecological cancers.</p><p>Rajith Kumar Reddy Rojoli (<span>[email protected]</span>)*</p><p><i>University of Liverpool</i></p><p>The use of long-acting (LA) antiretrovirals (ARVs) in children and alolescents could represent a valuable pharmacological option, to simplify regimens, reduce drug costs and improve adherence. Dose optimization in paediatic patients is complex and physiologically based pharmacokinetic (PBPK) modelling represents a predictive tool to identify promising dosing strategies. The paediatric patients were simulated using a mathematical description of covariance between demographics and tissue size expression of metabolic enzymes and processes regulating drug distribution. The aim of this study was to simulate the pharmacokinetics (PK) of LA ARVs - cobotegravir and rilpivirine in children and adolescents according to the differnt weight band categories recommended by World Health Organisation to identify optimal doses using PBPK modeling. These finding can be potentially used in children and adolescents adjusting the dosing based on weight, thus broadening the usage of ARVs and providing alternative strategies for treatment simplication.</p><p>Abbi Abdel Rehim (<span>[email protected]</span>; <span>[email protected]</span>)*</p><p><i>Manchester University</i></p><p>Tail anchored proteins are a subgroup of membrane proteins with a single transmembrane region at the C-terminus that is used to “anchor” the polypeptide into a lipid bilayer. Cytochrome b5 is a tail anchored protein that has been shown to insert into membranes via a mechanism that is both spontaneous and independent of any cytosolic factors. This ability for spontaneous insertion may provide a novel approach to attaching targeting ligands to liposomal drug delivery systems. Here, the capacity of the transmembrane region of cytochrome b5 to attach various N-terminal domains to liposomes is determined and the effect of the molecules upon the uptake of liposomes by human cells in culture is being investigated.</p><p>Alison Savage (<span>[email protected]</span>)*</p><p><i>University of Liverpool</i></p><p>Many active pharmaceutical ingredients exhibit poor water solubility, which often impacts bioavailability when taken as therapy. Recently, a strategy for formulating the antiretroviral Efavirenz into solid drug nanoparticles (SDNs) has been presented, with resulting products under investigation in human trials. Preparation of SDNs relies on emulsion-templated freeze-drying, involving a screening process using different polymers and surfactants. Whilst this method can identify suitable sets of excipients to stabilise the SDNs, the mechanisms behind this stabilising effect are not fully understood. A polymer and surfactant set that produce Efavirenz SDNs were investigated using isothermal titration calorimetry, to determine whether interactions between excipients and drug particle surface direct formation of nanoparticles. This was compared to excipient sets that failed to produce SDNs, to provide insight into any excipient effects. Data presented shows tentative correlations between positive interactions and SDN formation but additional study is required for broader understanding of the multi-variate mechanisms involved.</p><p>N. Lowri Thomas (<span>[email protected]</span>)*</p><p><i>Cardiff University School of Medicine</i></p><p>Rhythmic contraction of the myocardium depends on the controlled release of Ca<sup>2+</sup> from intracellular stores via cardiac ryanodine receptors (RyR2), and dysfunction of mutant RyR2s is linked with arrhythmia in the form of catecholaminergic polymorphic ventricular tachycardia (CPVT). The mechanisms of channel dysfunction have long thought to be ligand/accessory protein-dependent. However, using single channel analysis under minimal recording conditions we found that, in contrast to wild type (WT) and S2246L channels, N4104K mutant channels exhibited gating events in the absence of ligand, indicating an inherent effect on channel structure and function. Hidden Markov Modelling of the gating data showed that this was likely due to an increased susceptibility to enter a conformational state that favours subsequent opening. This suggests that the unliganded gating exhibited by N4104K channels promotes a heightened propensity for Ca<sup>2+</sup> release at the cellular level not seen with mutants which do not exhibit this fundamental gating defect.</p><p>Adam R Town (<span>[email protected]</span>)*</p><p><i>Department of Chemistry, University of Liverpool</i></p><p>Prolonged administration of drugs for long term conditions faces the issue of poor patient compliance when frequent repeated administration of drug is required, e.g. a daily oral dose. Pre-formed sustained release implants overcome this issue but require invasive surgery. In situ-forming implants (ISFI) are easier to administer, allow site specific delivery, and ease of manufacture, however ISFIs suffer from issues such as high burst release of drug, toxicity and stability of the system. We have synthesised PNIPAM nanogels which are able to rapidly aggregate after injection, in response to physiological conditions, to form a hydrophobic depot for the delivery of poorly water soluble drugs. The release rate of drug from the aggregate is tuneable, and enhanced when drug is used in solid drug nanoparticle form. Burst release is minimal despite high drug loading, and sustained release can be maintained for over 100 days.</p><p>Alexandra G. Vaideanu (<span>[email protected]</span>; <span>[email protected]</span>)*</p><p><i>Department of Engineering, University of Cambridge</i></p><p>Reference</p><p>[1] Setua, S., Ouberai, M., Piccirillo, S. G., Watts, C. & Welland, M. Cisplatin-tethered gold nanospheres for multimodal chemo-radiotherapy of glioblastoma. Nanoscale 6, 10865–10873 (2014)</p><p>Aviral Vatsa (<span>[email protected]</span>)*</p><p><i>University of Glasgow</i></p>","PeriodicalId":91547,"journal":{"name":"Journal of interdisciplinary nanomedicine","volume":"1 2","pages":"35-82"},"PeriodicalIF":0.0000,"publicationDate":"2016-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/jin2.14","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of interdisciplinary nanomedicine","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/jin2.14","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Shahd Abuhelal ([email protected])*
King's College London/Institute of Pharmaceutical Science
siRNA treatment can result in decreased protein expression and could be used to treat cancer or other diseases. Successful application depends on efficient delivery inside target cells. Here, we aim to design and optimise a nano-carrier suitable for siRNA delivery, with high encapsulation efficiency and stability for use in vitro and in vivo to target cancer.
Liposomes and pH-sensitive peptides assembled as ternary complex were investigated as siRNA delivery systems. Physicochemical characteristics (size, zeta potential, siRNA maintenance, release and aggregation) were tested. Cell uptake and luciferase knock down were evaluated in vitro, and some complexes tested for biodistribution in vivo.
Hydrodynamic size and zeta potential of the lipoplex, peptide complexes and ternary complexs were similar. Although lipoplexes showed better encapsulation, they were less stable in serum. Ternary complexes offered better protection for the siRNA. Improved cell uptake was seen for ternary complexes in comparison with peptide complex and lipoplex. Knock down studies revealed optimal effects ternary complexes, and preliminary in vivo experiments showed tumour accumulation of lipoplex.
These siRNA delivery vehicles appear promising for in vivo applications, and work is now focused on the improvement of cell targeting, in vitro and in vivo PK/PD.
Chris Adams ([email protected])*
Keele University
Magnetic nanoparticles (MNPs) are key translational platforms with the ability to label cells for non-invasive imaging and genetically engineer cells for release of therapeutic biomolecules. We show for the first time that application of magnetic fields can safely enhance MNP mediated labelling and genetic engineering of autologous canine olfactory mucosal cells (cOMCs), a key veterinary cell population for treatment of spinal injury in companion dogs. Crucially, the developed protocols were successfully combined with advanced minicircle DNA vectors to deliver brain derived neurotrophic factor (important in promoting nerve fibre outgrowth) to cOMCs. Minicircles have distinct advantages for clinical gene delivery due to their small size, lack of bacterial backbone and duration of transgene expression. Finally, we also show that MNP labelling can facilitate imaging of cOMCs encapsulated in implantable collagen hydrogels using non-invasive magnetic resonance imaging. A combination of these methodologies could enable translation of safe and effective cOMC transplantation strategies.
Mohammad Ahmad Abdallah Al-Natour ([email protected])*
University and Institution: University of Nottingham
Abstract
Recent years have witnessed unexpected growth of research on the medical applications of nanotechnology (nanomedicine), especially the use of nanoparticles (NPs) in the diagnosis and treatment of disease. Among these polymeric NPs have many advantages; they can be prepared from biocompatible FDA approved polymers, easily functionalized with smart ligands, and tailored to control the release of encapsulated drugs. However the impact of these NPs at the molecular and cellular levels has not been fully studied.
We have applied cell based metabolomics methodology to investigate the cellular metabolic changes in human-like macrophages after exposure to five different poly(lactic-co-glycolic acid (PLGA) NPs. The study revealed that all NPs induced oxidative stress and shift in energy metabolism from citric acid cycle to glycolysis. However none of them were toxic. Metabolites fold changes showed that PEG-PLGA NPs had the minor impact on the cellular metabolism.
Wejdan Al-Shakarchi ([email protected])*
Institute for Science and Technology in Medicine, Keele University
Abstract
Hepatocellular carcinoma accounts for 85% of liver cancers that originate in liver cells. This type of tumour is characterised by defective or ineffective apoptosis, which is considered to be the main cause of cancer progression. Cytochrome-C (heme protein) triggers mitochondrial apoptosis and is responsible for activation of the downstream caspase apoptosis pathway during cell death in tumour cells. However, there is a significant difficulty in the delivery of proteins through the cell membrane. Iron-gold hybrid nanoparticles (HNP-C) application offers a promising tool for cytochrome-c delivery into tumour cells and enhances the specific targeting of therapeutic particles to their site of action.
Anticancer drugs (doxorubicin, paclitaxel, oxaliplatin, vinblastine and vincristine) with different mechanisms of action were used to treat the HepG2 cells at specific concentrations to assess their IC50 values, and subsequently the cells were treated with each one of these drugs in combination with HNP-Cytochrome C showing a 10% growth inhibition alone in HepG2 cells.
The successful delivery of pro-apoptotic protein (cytochrome-C) using hybrid iron-oxide gold nanoparticles can be considered as a promising step in the liver cancer treatment by working in synergism pattern with anticancer drugs and significant decrease in the IC50 of each drugs combination against the HepG2 cells viability.
Ali Alazzo ([email protected])*
University of Nottingham/School of Pharmacy
Non-viral gene delivery systems have been investigated for many years; however, the successful clinical translation of this approach is still limited due to several biological and technical obstacles that should be overcome to prepare a successful vector. Highly branched and easily functionalized polymers have emerged as an attractive solution to address these barriers. In this context, hyperbranched polymers represent a promising alternative to dendrimers for their advantages in terms of cost that make synthesis more feasible and applicable for scale up and manufacturing. Here, we investigated the effect of histidine on the structure and gene delivery applications of thermally polymerized hyperbranched polylysine. The structural analysis indicated that the incorporation of histidine modulates the structure of hyperbranched polylysine to produce a more dendritic polymer with less flexible branches. Additionally, the results revealed that there was a negative correlation between the content of histidine in the polymers and their capability to condense and deliver nucleic acid.
Mohanad Alfahad ([email protected])*
Institute of Science and Technology in Medicine (ISTM), Keele University
Pancreatic cancer is the fourth main cancer in the western world. Gemcitabine treatment only proves effective in 23.8% of patients with pancreatic cancer. Nanotechnology can play an essential role by delivering anticancer drugs to the malignant cells in a targeted fashion,
In this part of the study, we have investigated the Prodrug attachment to hybrid nanoparticle surface via dative covalent linkage.
The HNP were synthesized, coated with PEI and gold. Prodrug of Gemcitabine was synthesized using established procedures.
Attachment of prodrugs on to HNP surface was quantified using reverse phase HPLC. In vitro drug release studies were carried out at different temperatures.
Novel prodrugs of gemcitabine were isolated and characterized. HNPs were synthesized successfully in the magnitude of 70 nm. Prodrug attachment to HNP was successful with as much as 5 mg mL-1 being detected. Drug release studies indicated that the formulation was stable over the range of temperatures tested.
Ali Alsuraifi ([email protected])*
Institute for Science and Technology in Medicine, Keele University, Keele ST5 5BG, UK
Abstract
A limitation associated with cancer treatment arises from the problems in directing highly cytotoxic agents to the diseased tissues, low solubility in aqueous media and poor bioavailability. Many drug delivery systems have been devised to address this problem, including thermoresponsive polymers. In this study, a novel HPMA-CO-AMPA-R thermoresponsive copolymer has been prepared to act as drug delivery system and to enhance the solubility of poor water-soluble drugs via grafted hydrophobic groups onto the primary amine group of APMA monomers using palmitoyl, dansyl, cholesteryl and 5-(4-chlorophenyl)-1,3,4- oxadiazole. The product characterization was carried out by FTIR, NMR and Zeta Sizer. Drug loading and release abilities of HPMA-CO-AMPA-R copolymers were determined by using HPLC.
Aurelien Trichet ([email protected])*
University of Oxford, Department of Materials
Within the last decade, optical resonators, thanks to their low mode volume and/or high finesse, have emerged as a promising avenue to isolate and measure real-time properties of single nanoparticles such as viruses or gold nanoparticles. Such trapping devices with sensing capabilities are on the verge of finding powerful applications in interdisciplinary science. However, the quest for a candidate bringing together in-situ detection, trapping and multiple quantitative measurements of the particle properties supported by a comprehensive understanding still remain elusive.
Patrick Ball ([email protected])*
Bangor University
Directed enzyme prodrug therapy (DEPT) is a form of cancer chemotherapy that involves the delivery of prodrug-activating enzymes to a tumour before administering a prodrug to the patient, resulting in a higher local toxicity than current chemotherapy strategies. The bacterial nitroreductase NfnB has been investigated for potential use in DEPT in combination wuth the CB1954 prodrug and this combination has even reached the clinical trial stage. A mojor limitation of this technology is the dose limiting toxicity of the CB1954 prodrug and as such other produgs need to be explored for use in DEPT strategies. The two novel mustard prodrugs, PR-104A and SN27686, developed at Auckland University, New Zealand, are the most promising prodrugs available and as such are currently being tested in combination with the NfnB enzyme using the novel gold-coated magnetic nanoparticle delivery system developed at Bangor University, Wales.
Mike Burgum ([email protected])*
Swansea University
Few-layer graphene (FLG), defined as possessing three or more atomic layers of graphene, is a revolutionary material stronger than diamond and more conductive than copper. The present study sought to assess the toxicological impact of 700 m2/g FLG flakes engineered with (i) no specific functionality, (ii) amine groups or (iii) carboxyl groups. Each FLG was then exposed to a representative human airway epithelial monoculture of 16HBE14o- cells.
Size and morphology of the flakes were characterised with scanning electron microscopy (SEM) and atomic force microscopy (AFM). Cell viability and chromosomal damage were assessed by relative population doubling (RPD) and the cytokinesis block micronucleus (CBMN) assay respectively.
FLG induced no significant cytotoxicity at any of the tested concentrations. In contrast, at sub-lethal concentrations, significant genotoxicity was induced by both non- and amine-functionalised FLG from 20 µg/ml whilst the carboxyl-functionalised flakes induced a significant response at 100 µg/ml.
Jake Casson ([email protected])*
University of Glasgow
Skeletal metastasis is prevalent in many cancers, in particular epithelial tumours (eg. breast cancer). It is now evident that, in the early stages of metastatic spread, disseminated tumour cells in the bone marrow undergo an extended period of growth arrest in response to the microenvironment, a phenomenon known as dormancy. Understanding the mechanism of transition from dormancy to a recurrent growth state is limited by the availability of physiologically relevant models. In this project we have developed a co-culture model to explore this transition, utilising 3D cell spheroids of both breast cancer cells and bone marrow mesenchymal stromal cells, co-cultured over a monolayer of intact or scratch wounded fibroblasts. The release of interleukin-6 (IL-6) has been documented when performing a scratch assay on fibroblasts. Our findings indicate the presence of IL-6 causes breast cancer cells to migrate out of the spheroid, indicating a switch from dormancy to an active growth state.
Dr Oliver Castell ([email protected])*
Cardiff University - College of Biomedical and Life Science, School of Pharmacy and Pharmaceutical Sciences
Droplet Interface Bilayers (DIBs) represent artificial mimics of the cell membrane suitable for biophysical studies and applications in synthetic biology. Self-assembly of lipid at a droplet water-oil interface creates a lipid monolayer, and the contacting of two such interfaces forms a bilayer. Functional membrane proteins can be reconstituted into these bilayers. Total Internal Reflection Fluorescence (TIRF) microscopy can be used to make dynamic single molecule measurements, allowing the unpicking of intrinsic molecular mechanisms of the membrane, with a level of insight not afforded by traditional ensemble techniques. Here we highlight the use of droplet interface bilayers to make optical measurements of protein function and to make single molecule measurements on the dynamics of membrane organisation. Such measurements in well controlled model systems serve to increase our understanding of the membrane at the molecular level, providing unique insight into the nanoscale mechanisms underpinning complex cellular functions.
Dr Helen Cauldbeck ([email protected])*
University of Liverpool, Department of Chemistry
Complicated cases of retinal detachment are treated with silicone oil (SiO) tamponades which can potentially be used as drug reservoirs. Various methodologies to develop a sustained and controlled drug release, for a clinically-relevant release period, 6-8 weeks, from SiO tamponades were investigated. The solubility and release of drugs from SiO was assessed using radioisotope techniques. The formation of prodrugs and novel polymer architectures with hydrophilic components that show considerable miscibility. Further additive development of SiO may produce enhanced and tailored release profiles. Cytotoxicity of drugs and synthesised additives were studied against an adult retinal pigment epithelium cell line (ARPE-19).
Natalie Cureton ([email protected])*
University and Institution: Insitute of Human Development, University of Manchester
Abstract
Pregnancy complications are often attributed to poor uteroplacental blood flow, but the risk of systemic side-effects hinders therapeutic intervention. We have used novel peptide-conjugated liposomes that selectively bind to the uteroplacental vasculature to deliver the vasodilator compound SE175 to pregnant endothelial nitric oxide synthase knockout mice, a well-characterised model of fetal growth restriction (FGR).
Liposomes containing SE175 or PBS were prepared by lipid film hydration and targeting peptides coupled to the liposomal surface. Vehicle control, free SE175, PBS- or SE175-containing liposomes were intravenously injected on embryonic (E) days 11.5, 13.5, 15.5 and 17.5. Animals were sacrificed at E18.5 and fetal and placental weights recorded.
Targeted delivery of SE175 significantly increased fetal weight compared to vehicle control but no other treatment groups, whilst significantly decreasing placental weight, indicating improved placental efficiency.
These data suggest that selective delivery of SE175 to the uteroplacental vasculature may represent a novel treatment for FGR.
Christopher David ([email protected])*
University of Liverpool, Department of Molecular and Clinical Pharmacology
Polydendrons, a novel nanomaterial, were characterised and subjected to in vitro toxicological and immunological tests. Four polydendrons; comprising two ratios of G2 dendron initiator to PEG, in two sizes, were measured for size and surface charge in various media via dynamic light scattering and zeta potential. Sample sterility, cytotoxicity, ROS generation, glutathione reduction, and influence on autophagy were assessed. Notably the smaller 50:50 polydendron generated 1.35- and 9.64-fold increases in IL-1β and TNFα respectively compared to an untreated control. Also, a 1.53-fold increase in leukocyte proliferation was observed, with no significant effects on plasma coagulation, complement activation, or haemolytic potential.
Ruiz de Angulo ([email protected])*
CIC biomaGUNE
Abstract
Many pathogens and cancer cells have evolved mechanisms to evade the host immune response, creating an urgent need for developing new, safe and effective vaccine technologies.[1] Herein we designed PEGylated magnetite-filled nanoparticles as delivery systems to direct tumour antigens and/or adjuvants to lymph nodes (LNs).
References
[1] D. M. Morens, G. K. Folkers, A. S. Fauci, Nature 2004, 430, 242–9.
[2] A. Ruiz-de-Angulo, A. Zabaleta, V. Gómez-Vallejo, J. Llop, J. C. Mareque-Rivas, ACS Nano 2016, 10, 1602–18.
Stephanie Edwards ([email protected])*
University of Liverpool, Chemistry Department
Amaia Garaikoetxea ([email protected])*
CIC biomaGUNE
Platinum (II) complexes such as cisplatin are still among the best chemotherapeutic agents for the treatment of a variety of tumours.1 Their clinical use, however, has important drawbacks (resistance, efficacy etc.) and is dose-limited by systemic toxicity. A new generation of Pt(IV) prodrugs are showing considerable potential for overcoming some of these issues.2 The use of nanoparticles as nanocarries offers great advantages both to improve the delivery and therapeutic index of these prodrugs and to monitor drug targeting by multimodal imaging.
[1] D. M. Morens, G. K. Folkers, A. S. Fauci, Nature2004, 430, 242–9.
[2] A. Ruiz-de-Angulo, A. Zabaleta, V. Gómez-Vallejo, J. Llop, J. C. Mareque-Rivas, ACS Nano2016, 10, 1602–18.
Nina Gómez Blanco ([email protected])*
CIC biomaGUNE
The main clinical application of iron oxide nanoparticles (IONPs) is as contrast agents for Magnetic Resonance Imaging (MRI). Furthermore, they can be engineered for developing effective theranostic nanosystems that integrate multimodal imaging and cancer therapy.1 In this context, we are exploring IONPs labelled with 67Ga in combination with platinum anticancer prodrugs to create a SPECT-MR imaging vehicles which can deliver cisplatin in the reducing environment of tumors. In order to achieve optimal r2 relaxivity,2 we prepared IONPs with different shapes and sizes and solubilised them in water by encapsulation within PEG-phospholipids micelles.
[2] Lee N.; Choi Y.; Lee Y.; Park M.; Kyung Moon W.; Hong Choi S.; Hyeon T.; Nano Lett. 2012, 12, 3127-3131.
Faye Hern ([email protected])*
University of Liverpool
James Hobson ([email protected])*
University of Liverpool
Oil-in-Water Nanoemulsions loaded with either efavirenz or lopinavir were prepared using homogenisation/solvent evaporation technique to increase the concentration of drug in an aqueous environment. The ability of NEs to permeate intestinal barriers was assessed using Caco-2 transwell system, EFV and LPV loaded NEs were compared with aqueous solutions. NE LPV had significantly increased permeation compared to aqueous LPV, with apparent permeability (Papp) of 6.4 x 10-5 cm/s vs 2.7 x 10-6 cm/s (p= <0.05). Comparable results being observed for NE EFV compared to aqueous EFV, with Papp values of 1.1 x 10-5 cm/s and 8.2 x 10-6 cm/s respectively (p=<0.05).
David Howard ([email protected])*
Swansea University Medical School
Antibody drug conjugates (ADCs) are an emerging class of anti-cancer agents showing great promise in the treatment of advanced cancers. ADCs consist of a tumour-targeting monoclonal antibody conjugated to a cytotoxic payload via blood-stable linkers. These prodrugs bind antigens on the tumour cell surface, are internalised, and upon release of their toxic payloads, induce cell death. Despite the over fifty ADCs currently undergoing clinical trials, only a limited number of different payloads are featured. In light of the challenges inter- and intra-tumour heterogeneity and drug resistance pose to cancer treatment, the expansion of the ADC war chest with payloads operating by diverse mechanisms could prove important in improving ADC efficacies. Herein we describe our efforts to identify and evaluate novel ADC payloads. We report on the anti-tumour effects of a novel ADC payload candidate showing promising efficacy in both type I and II endometrial cancer cell-lines.
Wei-Hsin Hsu ([email protected])*
University of Nottingham
In polymeric gene delivery, a biodegradable versatile material with low toxicity has been a predominant criterion. Polyphosphazene is an artificial bioerodible polymer, with potential to generate ample derivatives for pharmaceutical purpose. Herein, we explored the use of a known allylamine-substituted polyphosphazene as a precursor and presented flexible click-chemistry for avoiding unwanted side reactions. We designed a mixed-complex with cationic and anionic polyphosphazenes, not only for stably binding pDNA but also for controlled release of pDNA in endosomal environment. While Mix-plex incubated in the acid environment, the TEM images showed separate phases inside the nanoscale complex, likely indicating pH-induced structural change might facilitate release of pDNA. In transfection of 3D-spheroid of U87MG, Mix-plex can promote gene-transfection into tumour cells, compared with the conventional polyplex. In summary, this polyphosphazene-based nano-complex not only presented functional modification for controlled gene release as well as provided various promising derivatives in gene delivery.
Dr Yazan S. Khaled ([email protected])*
University of Leeds, Nanotechnology Group
Abstract:
Background: There is a need for real-time imaging of colorectal cancer (CRC) to allow tailored surgery. Fluorescent nanoparticles may offer a solution with non-immunoglobulin (non-Ig) targeting molecules possessing advantages over antibodies.
Aim: We aimed to develop and test fluorescent silica nanoparticles targeted against CRC using an anti-carcinoembryonic antigen (CEA) Adhiron (Ad).
Methods: Anti-CEA or control Ads were conjugated to silica nanoparticles. Binding of CEA-Ad or control nanoparticles to CRC cells was quantified in vitro using confocal microscopy.
Results: Dye-doped-(NIR664)-silica nanoparticles were synthesised with a median diameter of ~60 nm. CEA-targeted, SMCC-conjugated nanoparticles, but not control nanoparticles, allowed strong tumour-specific fluorescence when incubated with LoVo (p=0.021), LS174T (p=0.041), and HT29 (p=0.03) respectively. There was no significant difference in fluorescence for CEA-Adhiron vs. CEA-Antibody targeted nanoparticles.
Conclusion: We are the first to demonstrate specific, in vitro imaging of CRC cells using Adhiron-targeted fluorescent nanoparticles. CEA-Adhiron appears to be a suitable non-Ig targeting molecule.
Rachita Lahri ([email protected])*
Institute of Pharmaceutical Science, School of Biomedical Sciences, King's College London
Microwave imaging is a new imaging modality which has attracted a lot of attention recently. Microwave imaging is a technique that exploits the dielectric contrast at microwave frequencies between malignant and the healthy tissues. Microwave – frequency dielectric properties difference between malignant and healthy adipose dominated tissue in the breast is as large as 10:1. However the contrast between malignant and normal glandular/fibro-connective tissue in the breast is no more than 10%. This contrast can be improved by the use of various nanoparticles. Dielectric properties of silicon dioxide, titanium dioxide, zinc oxide and different carbon nanotubes have been measured in water for this study. A significant increase was seen within the dielectric properties when carbon nanotubes were added in water. On the other hand, there was no significant increase seen within the dielectric properties when silicon dioxide, titanium dioxide and zinc oxide were added in water.
Diana Moreira Leite ([email protected])*
Institute of Biomedical and Biomolecular Sciences, School of Pharmacy and Biological Sciences, University of Portsmouth
Brain diseases are responsible for 12% of global deaths and their treatment could benefit from the use of highly potent and specific pharmaceuticals with low inherent toxicity and immunogenicity such as neuropeptides 1. However, for neuropeptide therapies to be realised, peptides need to be able to cross the blood-brain barrier (BBB) and possess enhanced enzymatic stability to ensure adequate brain bioavailability. Lipidisation of peptides has been proven to be a useful strategy to enhance enzymatic stability and BBB permeability, while increasing the amphiphilicity of neuropeptides allows their self-assembly in well-defined nanostructures 2,3. We have developed a neuropeptide amphiphile able to self-assemble and entrap brain impermeable drugs, which; possess enhanced stability to enzymatic degradation, permeates the BBB (all human in vitro BBB model) and targets receptors overexpressed in glioblastoma cells resulting in a novel targeted nanomedicine with a strong anti-proliferative and apoptotic effects in vitro. The proposed nanomedicine can be readily translated and proof of concept in an animal model is under way.
References
[1] Lalatsa, A., et al. Molecular Pharmaceutics 2014, 11, 1081-1093.
[2] Lalatsa, A., et al. Molecular Pharmaceutics 2012, 9, 1665-1680.
[3] Lalatsa, A., et al. Journal of Controlled Release 2015, 197, 87-96.
Martin Levere ([email protected])*
Department of Chemistry, University of Liverpool
Edyta Lewandowska ([email protected])*
University of Liverpool, Department of Chemistry, UK
Natasha Lewis ([email protected])*
University of Glasgow
Wenwei Ma ([email protected])*
University of Lincoln
Conjugation of biomolecules to nanoparticles can be achieved using well-established chemistries. However, when it comes to structurally complex molecules such as proteins, their diversity makes it difficult to find a unique chemical cross-linking method that consistently produce functional conjugates. Therefore, protocols for immobilisation have to be empirically and tediously optimised case-by-case. Passive adsorption is a straightforward method for decoration of nanoparticles but unfortunately the adsorbed protein is thought to undergo denaturation and may not be uniformly oriented.
To address this, we are developing intermediate designer proteins that adsorb onto gold nanoparticles and carry a domain which specifically binds to an affinity tag. An arbitrary protein of interest which presents the tag can bind the functionalised particles by simple mixing, with reduced chance to undergo denaturation. Importantly, there is no need for optimisation of the conditions, as these are only determined by the affinity system and not by a nanoparticle-protein interaction.
Shijoy Mathew ([email protected])*
University of Glasgow
The human body is complex and prone to deterioration. With advances in medicine and the resultant increased life expectancy, there are several significant age-related conditions involving bone or cartilage deterioration and damage, primarily osteoarthritis and osteoporosis. Regeneration of these tissues via mesenchymal stem cells (MSCs) in the bone marrow is an on-going challenge.
The use of nanoparticles as a delivery platform in medicine is gaining recognition, due to the benefits conferred by their small size, non-toxicity and multi-valency, which allow for a safer and customizable method of delivery.
This project aims to use gold nanoparticles to deliver antagomirs (anti-miRNAs) to MSCs, with the aim of manipulating key miRNAs involved in MSC differentiation. MiRNAs are short sequenced RNAs that are involved in the regulation of nearly 30% of the genes in the body. This project aims to exploit their function to promote MSC differentiation into bone or cartilage cells.
William McDaid ([email protected])*
Queen's University Belfast, School of Pharmacy
The monoclonal antibody Cetuximab (CTX) has demonstrated limited efficacy in the clinic due to activating mutations which allow cancerous cells to acquire resistance. Due to outstanding success as a targeting agent, this study investigates whether CTX functions better as a targeting agent for drug-loaded nanoparticles (NPs) rather than a monotherapy against CTX-resistant cells. Cancer cells with different K-Ras mutations (known to mediate CTX resistance) were selected and the influence of CTX nanoconjugation was assessed with regards to NP uptake and drug delivery. The chemotherapeutic drug of choice in this study was the topoisomerase I inhibitor, camptothecin (CPT), which induces DNA damage in cancer cells. It was seen that CTX facilitated preferential NP uptake and CPT delivery to cells much more effectively than NPs with no surface modification. This was evident by an elevated level of executioner caspase activation and a higher incidence of apoptosis. These results support the premise that CTX is more competent acting as part of NP conjugate system rather than alone as a monotherapy.
Ciarán M. Maguire ([email protected])*
University of Dublin, Trinity College
Abstract
The size-dependent optical properties of Quantum Dots (QDs) are frequently exploited for use in medical imaging and labelling applications. Similarly, they elicit profound size-dependent anticoagulant properties, a focus for our research.
References
[1] Graf, N.; Lippard, S. J. Adv. Drug Delivery Rev.2012, 64, 993–1004.
[3] Hernández-Gil, J.; Cobaleda-Siles, M.; Zabaleta, A.; Salassa, L.; Calvo, J.; Mareque-Rivas, J. C. Adv. Healthcare Mat.2015, 4, 1034–1042.
Tahereh Tohidi Moghadam, Assistant Professor ([email protected]; [email protected])*
Tarbiat Modares University, Tehran, Iran
Abstract
David Morse ([email protected])*
University of Cambridge, Department of Engineering - Nanoscience Centre
Adeolu Oluwasanmi ([email protected])*
Institute for Science and Technology in Medicine, Keele University
Abstract
Pancreatic cancer remains the deadliest form of cancer in terms of its survival rate of only 3.7% after 5 years. To ensure the complete removal of adenocarcinomas of the pancreas, chemotherapy and highly invasive surgery has to be employed which is not possible in many of the elderly patients diagnosed with pancreatic cancer. The treatment of cancer can be multistep but the effects on the patients wellbeing can accumulate until treatment is no longer a viable option.
Nashwa Mahmoud Osman ([email protected])*
Liverpool John Moores University, Pharmacy and Biomolecular Sciences
Belen Pan-Castillo ([email protected])*
Swansea University
Abstract
Endometrial cancer is the most common gynaecological malignancy with incidence rates in Wales (25%) higher than in Europe (14%) and North American (16%). Wales presents the worst mortality rate (4.9%) among the UK countries (3.9%). Therefore, new therapeutics are urgently needed to improve survival rates.
Antibody drug conjugates (ADC) consist of a monoclonal antibody attached to a cytotoxic drug through a linker, having the ability to target and kill cancer cells only, while avoiding the widespread destruction of healthy cells typical of traditional chemotherapy. A novel ADC invented by RBGO academics and codename SNIPER, targets a protein expressed in uterine and ovarian cancers and absent in healthy tissue. Our data indicate SNIPER induces cell death of endometrial cancer cells more effectively than the current ADC in clinical use (Herceptin-ADC). This project aims to explore SNIPER safety and efficacy against gynaecological cancers, as an innovative solution to a current health problem.
Anil Patel ([email protected])
University of Glasgow
Abstract
Using nanoparticles to induce cancer cell hyperthermia and death is a new and developing technique. Cancer cell vulnerabilities to specific high temperatures (42-45 °C) are exploited through localised heating of Gold nanoparticles (GNPs). These ‘nanoscale heaters’ absorb and convert near infrared (NIR) light into heat via their surface plasmon resonance, thus inducing hypothermia, which in turn induces apoptosis driven cancer cell death.
In this study, Gold nanoprisms and nanorods were cultured with cancer cell lines, both in 2D monolayer and 3D multicellular tumoroids. Following initial biocompatibility testing, these nanostructures were shown to have no significant effect on cell viability (MTT). SEM and TEM scanning demonstrated clear internalisation of both nanoprisms and rods after 1 hr culture. Utilising a 1 W continuous wave 1064nmNR laser, both monolayer and tumoroid cultures were irradiated, inducing significant cell death monitored via live/dead assay. Subsequent RNA analysis via fluidigm suggested up-regulation of key apoptotic genes, supporting cancer cell apoptosis as a result of hyperthermia induction.
Simone Pisano ([email protected])*
Swansea University
Nanoparticles, due to their size and structure, offer the possibility of targeted drug delivery and an innovative and promising approach in the treatment of solid tumour cancers. It is effectively known that free drugs often fail to enter tumour site and exhibit burdensome patient side effects. This project focuses on the fabrication of three nanoparticle formulations (Pluronic F127, PLGA and Chitosan) and their physical and chemical characterization before and after encapsulation of a hydrophobic epidrug, SAHA (a HDAC inhibitor). Epigenetic drugs have been broadly studied on different cancer types. Here we demonstrate epidrug efficacy in an in vitro model of endometrial cancer, the most common gynaecological tumour. Free drug and nanoparticle encapsulated forms are directly comparable, demonstrating an effective encapsulation and therapeutic approach which may be a valid and viable delivery method for future applications in all gynaecological cancers.
Rajith Kumar Reddy Rojoli ([email protected])*
University of Liverpool
The use of long-acting (LA) antiretrovirals (ARVs) in children and alolescents could represent a valuable pharmacological option, to simplify regimens, reduce drug costs and improve adherence. Dose optimization in paediatic patients is complex and physiologically based pharmacokinetic (PBPK) modelling represents a predictive tool to identify promising dosing strategies. The paediatric patients were simulated using a mathematical description of covariance between demographics and tissue size expression of metabolic enzymes and processes regulating drug distribution. The aim of this study was to simulate the pharmacokinetics (PK) of LA ARVs - cobotegravir and rilpivirine in children and adolescents according to the differnt weight band categories recommended by World Health Organisation to identify optimal doses using PBPK modeling. These finding can be potentially used in children and adolescents adjusting the dosing based on weight, thus broadening the usage of ARVs and providing alternative strategies for treatment simplication.
Tail anchored proteins are a subgroup of membrane proteins with a single transmembrane region at the C-terminus that is used to “anchor” the polypeptide into a lipid bilayer. Cytochrome b5 is a tail anchored protein that has been shown to insert into membranes via a mechanism that is both spontaneous and independent of any cytosolic factors. This ability for spontaneous insertion may provide a novel approach to attaching targeting ligands to liposomal drug delivery systems. Here, the capacity of the transmembrane region of cytochrome b5 to attach various N-terminal domains to liposomes is determined and the effect of the molecules upon the uptake of liposomes by human cells in culture is being investigated.
Alison Savage ([email protected])*
University of Liverpool
Many active pharmaceutical ingredients exhibit poor water solubility, which often impacts bioavailability when taken as therapy. Recently, a strategy for formulating the antiretroviral Efavirenz into solid drug nanoparticles (SDNs) has been presented, with resulting products under investigation in human trials. Preparation of SDNs relies on emulsion-templated freeze-drying, involving a screening process using different polymers and surfactants. Whilst this method can identify suitable sets of excipients to stabilise the SDNs, the mechanisms behind this stabilising effect are not fully understood. A polymer and surfactant set that produce Efavirenz SDNs were investigated using isothermal titration calorimetry, to determine whether interactions between excipients and drug particle surface direct formation of nanoparticles. This was compared to excipient sets that failed to produce SDNs, to provide insight into any excipient effects. Data presented shows tentative correlations between positive interactions and SDN formation but additional study is required for broader understanding of the multi-variate mechanisms involved.
N. Lowri Thomas ([email protected])*
Cardiff University School of Medicine
Rhythmic contraction of the myocardium depends on the controlled release of Ca2+ from intracellular stores via cardiac ryanodine receptors (RyR2), and dysfunction of mutant RyR2s is linked with arrhythmia in the form of catecholaminergic polymorphic ventricular tachycardia (CPVT). The mechanisms of channel dysfunction have long thought to be ligand/accessory protein-dependent. However, using single channel analysis under minimal recording conditions we found that, in contrast to wild type (WT) and S2246L channels, N4104K mutant channels exhibited gating events in the absence of ligand, indicating an inherent effect on channel structure and function. Hidden Markov Modelling of the gating data showed that this was likely due to an increased susceptibility to enter a conformational state that favours subsequent opening. This suggests that the unliganded gating exhibited by N4104K channels promotes a heightened propensity for Ca2+ release at the cellular level not seen with mutants which do not exhibit this fundamental gating defect.
Adam R Town ([email protected])*
Department of Chemistry, University of Liverpool
Prolonged administration of drugs for long term conditions faces the issue of poor patient compliance when frequent repeated administration of drug is required, e.g. a daily oral dose. Pre-formed sustained release implants overcome this issue but require invasive surgery. In situ-forming implants (ISFI) are easier to administer, allow site specific delivery, and ease of manufacture, however ISFIs suffer from issues such as high burst release of drug, toxicity and stability of the system. We have synthesised PNIPAM nanogels which are able to rapidly aggregate after injection, in response to physiological conditions, to form a hydrophobic depot for the delivery of poorly water soluble drugs. The release rate of drug from the aggregate is tuneable, and enhanced when drug is used in solid drug nanoparticle form. Burst release is minimal despite high drug loading, and sustained release can be maintained for over 100 days.
Alexandra G. Vaideanu ([email protected]; [email protected])*
Department of Engineering, University of Cambridge
Reference
[1] Setua, S., Ouberai, M., Piccirillo, S. G., Watts, C. & Welland, M. Cisplatin-tethered gold nanospheres for multimodal chemo-radiotherapy of glioblastoma. Nanoscale 6, 10865–10873 (2014)
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