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6. Controlled synthesis and properties of neoglycoconjugates

Author

Spain, Sebastian G.

Subjects
547.78
Abstract

Glucosyl and galactosyl bearing methacrylates were synthesised using a combination of well known carbohydrate chemistry and ultrasonic chemistry. Polymerisation of these monomers by aqueous reversible addition-fragmentation chain transfer polymerisation yielded glycosylated polymers in high yield with a high degree of control over molecular weight and narrow polydispersity. Polymers of varying levels of glycosylation could be achieved through addition of a comonomer. Block copolymers were synthesised through sequential monomer addition. Binding studies of these polymers to Ricinus communis agglutinin 120 by both isothermal titration calorimetry and surface plasmon resonance found a high degree of molecular weight dependence on avidity. Studies also suggest that the increase in avidity through multivalency is due to both simultaneous binding to multiple receptors and the increased probability of binding due to the high local concentration of ligands. Polymers synthesised have been used in the synthesis of glycosylated gold nano-particles. Some degree of control over nanoparticle size was achieved through adjustment of the gold:polymer ratio but was found to be limited. Agglutination assays show the particles display specific lectin binding but in vitro cell studies were unable to give conclusive information regarding the uptake of particles into cells.

Published
2009

9. Synthesis of 5-Fluorouracil Polymer Conjugate and 19 F NMR Analysis of Drug Release for MRI Monitoring.

Author

Alhaidari, Laila M. and Spain, Sebastian G.

Subjects
*MAGNETIC resonance imaging, *POLYMERIZATION, *MOLECULAR size, *CONTRAST media, *DRUG monitoring, *POLYMERS
Abstract

To monitor the release of fluorinated drugs from polymeric carriers, a novel 19F MRI enzyme-responsive contrast agent was developed and tested. This contrast agent was prepared by conjugation of 5-fluorouracil (5-FU) to hyperbranched poly(N,N-dimethylacrylamide) (HB-PDMA) via an enzyme-degradable peptide linker. Due to the different molecular sizes, the release of 5-FU from the 5-FU polymer conjugate resulted in a sufficiently substantial difference in spin-spin T2 19F NMR/MRI relaxation time that enabled differentiating between attached and released drug states. The 5-FU polymer conjugate exhibited a broad signal and short T2 relaxation time under 19F NMR analysis. Incubation with the enzyme induced the release of 5-FU, accompanied by an extension of T2 relaxation times and an enhancement in the 19F MRI signal. This approach is promising for application in the convenient monitoring of 5-FU drug release and can be used to monitor the release of other fluorinated drugs. [ABSTRACT FROM AUTHOR]

Published
2023
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15. Polyvalent Diazonium Polymers Provide Efficient Protection of Oncolytic Adenovirus Enadenotucirev from Neutralizing Antibodies while Maintaining Biological Activity In Vitro and In Vivo

Author

Francini, Nora, primary, Cochrane, Daniel, additional, Illingworth, Sam, additional, Purdie, Laura, additional, Mantovani, Giuseppe, additional, Fisher, Kerry, additional, Seymour, Leonard W., additional, Spain, Sebastian G., additional, and Alexander, Cameron, additional

Published
2019
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19. Phosphonium polymethacrylates for siRNA delivery: effect of polymer and RNA structural parameters on polyplex assembly and gene knockdown

Author

Loczenski Rose, Vanessa, Shubber, Saif, Sajeesh, S., Spain, Sebastian G., Puri, Sanyogitta, Allen, Stephanie, Lee, Dong-Ki, Winkler, G. Sebastiaan, and Mantovani, Giuseppe

Abstract

Synthetic polymers containing quaternary phosphonium salts are an emerging class of materials for the delivery of oligo/polynucleotides. In this work, cationic phosphonium salt-containing polymethacrylates –and their corresponding ammonium analogues– were synthesized by RAFT polymerization. Both the nature of the charged heteroatom (N vs. P) and the length of the spacer separating the cationic units along the polymer backbone (oxyethylene vs. trioxyethylene) were systematically varied. Polymers efficiently bound siRNA at N+/P- or P+/P- ratios of 2 and above. At a 20:1 ratio, small polyplexes (Rh: 4-15 nm) suitable for cellular uptake were formed that displayed low cytotoxicity. Whilst siRNA polyplexes from both ammonium and phosphonium polymers were efficiently internalised by GFP-expressing 3T3 cells, no knockdown of GFP expression was observed. However, 65% Survivin gene knockdown was observed when short interfering RNA (siRNA) was replaced with novel, multimerised long interfering liRNA (liRNA) in HeLa cells, demonstrating the importance of RNA macromolecular architecture on RNA-mediated gene silencing.

Published
2015

20. Control of aggregation temperatures in mixed and blended cytocompatible thermoresponsive block co-polymer nanoparticles

Author

Foralosso, Ruggero, primary, Moir, Lee, additional, Mastrotto, Francesca, additional, Sasso, Luana, additional, Tchoryk, Aleksandra, additional, Selo, Amjad, additional, Grabowska, Anna, additional, Ashford, Marianne B., additional, Aylott, Jonathan, additional, Gellert, Paul R., additional, Spain, Sebastian G., additional, and Alexander, Cameron, additional

Published
2017
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22. Medium-Chain Fatty Acids Released from Polymeric Electrospun Patches Inhibit Candida albicansGrowth and Reduce the Biofilm Viability

Author

Clitherow, Katharina H., Binaljadm, Tahani M., Hansen, Jens, Spain, Sebastian G., Hatton, Paul V., and Murdoch, Craig

Abstract

Oral candidiasis is a very common oral condition among susceptible individuals, with the main causative organism being the fungus Candida albicans. Current drug delivery systems to the oral mucosa are often ineffective because of short drug/tissue contact times as well as increased prevalence of drug-resistant Candidastrains. We evaluated the potency of saturated fatty acids as antifungal agents and investigated their delivery by novel electrospun mucoadhesive oral patches using agar disk diffusion and biofilm assays. Octanoic (C8) and nonanoic (C9) acids were the most effective at inhibiting C. albicansgrowth on disk diffusion assays, both in solution or when released from polycaprolactone (PCL) or polyvinylpyrrolidone/RS100 (PVP/RS100) electrospun patches. In contrast, dodecanoic acid (C12) displayed the most potent antifungal activity against pre-existing C. albicansbiofilms in solution or when released by PCL or PVP/RS100 patches. Both free and patch-released saturated fatty acids displayed a significant toxicity to wild-type and azole-resistant strains of C. albicans. These data not only provide evidence that certain saturated fatty acids have the potential to be used as antifungal agents but also demonstrate that this therapy could be delivered directly to Candida-infected sites using electrospun mucoadhesive patches, demonstrating a potential new therapeutic approach to treat oral thrush.

Published
2020
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27. Polyvalent Diazonium Polymers Provide Efficient Protection of Oncolytic Adenovirus Enadenotucirev from Neutralizing Antibodies while Maintaining Biological Activity In Vitroand In Vivo

Author

Francini, Nora, Cochrane, Daniel, Illingworth, Sam, Purdie, Laura, Mantovani, Giuseppe, Fisher, Kerry, Seymour, Leonard W., Spain, Sebastian G., and Alexander, Cameron

Abstract

Oncolytic viruses offer many advantages for cancer therapy when administered directly to confined solid tumors. However, the systemic delivery of these viruses is problematic because of the host immune response, undesired interactions with blood components, and inherent targeting to the liver. Efficacy of systemically administered viruses has been improved by masking viral surface proteins with polymeric materials resulting in modulation of viral pharmacokinetic profile and accumulation in tumors in vivo. Here we describe a new class of polyvalent reactive polymer based on poly(N-(2-hydroxypropyl)methacrylamide) (polyHPMA) with diazonium reactive groups and their application in the modification of the chimeric group B oncolytic virus enadenotucirev (EnAd). A series of six copolymers with different chain lengths and density of reactive groups was synthesized and used to coat EnAd. Polymer coating was found to be extremely efficient with concentrations as low as 1 mg/mL resulting in complete (>99%) ablation of neutralizing antibody binding. Coating efficiency was found to be dependent on both chain length and reactive group density. Coated viruses were found to have reduced transfection activity both in vitroand in vivo, with greater protection against neutralizing antibodies resulting in lower transgene production. However, in the presence of neutralizing antibodies, some in vivotransgene expression was maintained for coated virus compared to the uncoated control. The decrease in transgene expression was found not to be solely due to lower cellular uptake but due to reduced unpackaging of the virus within the cells and reduced replication, indicating that the polymer coating does not cause permanent inactivation of the virus. These data suggest that virus activity may be modulated by the appropriate design of coating polymers while retaining protection against neutralizing antibodies.

Published
2019
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33. Synthesis and characterization of variable conformation pH responsive block co-polymers for nucleic acid delivery and targeted cell entry

Author

Matini, Teresa, primary, Francini, Nora, additional, Battocchio, Anna, additional, Spain, Sebastian G., additional, Mantovani, Giuseppe, additional, Vicent, Maria J., additional, Sanchis, Joaquin, additional, Gallon, Elena, additional, Mastrotto, Francesca, additional, Salmaso, Stefano, additional, Caliceti, Paolo, additional, and Alexander, Cameron, additional

Published
2014
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45. Enhanced uptake of nanoparticle drug carriers viaa thermoresponsive shell enhances cytotoxicity in a cancer cell lineElectronic supplementary information (ESI) available. See DOI: 10.1039/c2bm00184e

Author

Abulateefeh, Samer R., Spain, Sebastian G., Thurecht, Kristofer J., Aylott, Jonathan W., Chan, Weng C., Garnett, Martin C., and Alexander, Cameron

Abstract

Polymer particles consisting of a biodegradable poly[lactide-co-glycolide] (PLGA) core and a thermoresponsive shell have been formulated to encapsulate the dye rhodamine 6G and the potent cytotoxic drug paclitaxel. Cellular uptake of these particles is significantly enhanced above the thermal transition temperature (TTT) of the polymer shells in the human breast carcinoma cell line MCF-7 as determined by flow cytometry and fluorescence microscopy. Paclitaxel-loaded particles display reduced and enhanced cytotoxicity below and above the TTT respectively compared to unencapsulated drug. The data suggests a potential route to enhanced anti-cancer efficacy through temperature-mediated cell targeting.

Published
2013
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46. Programmable polymer-DNA hydrogels with dual input and multiscale responsesElectronic supplementary information (ESI) available: Detailed methods for synthesis, rheology and further figures depicting particle transport across gels. See DOI: 10.1039/c3bm60126a

Author

Sicilia, Giovanna, Grainger-Boultby, Christine, Francini, Nora, Magnusson, Johannes P., Saeed, Aram O., Fernández-Trillo, Francisco, Spain, Sebastian G., and Alexander, Cameron

Abstract

Combination switchable polymer-DNA hydrogels have been synthesized to respond to both a specific oligonucleotide recognition signal and a non-specific but biorelevant environmental trigger. The hydrogels exhibit rheological properties that can be modulated through interaction with complementary DNA strands and/or reduction. Furthermore, individual and combined oligonucleotide recognition and reduction responses allow control over pore sizes in the gel, enabling programmable release and transport of objects ranging from the nano- to micro-scale.

Published
2013
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47. Mucoadhesive Electrospun Fibre-Based Technologies for Oral Medicine.

Author

Edmans, Jake G., Clitherow, Katharina H., Murdoch, Craig, Hatton, Paul V., Spain, Sebastian G., and Colley, Helen E.

Subjects
ORAL medicine, DRUG delivery devices, TARGETED drug delivery, ORAL diseases, THERAPEUTICS, ANALGESIA, SUMATRIPTAN, BIOMEDICAL adhesives
Abstract

Oral disease greatly affects quality of life, as the mouth is required for a wide range of activities including speech, food and liquid consumption. Treatment of oral disease is greatly limited by the dose forms that are currently available, which suffer from short contact times, poor site specificity, and sensitivity to mechanical stimulation. Mucoadhesive devices prepared using electrospinning offer the potential to address these challenges by allowing unidirectional site-specific drug delivery through intimate contact with the mucosa and with high surface areas to facilitate drug release. This review will discuss the range of electrospun mucoadhesive devices that have recently been reported to address oral inflammatory diseases, pain relief, and infections, as well as new treatments that are likely to be enabled by this technology in the future. [ABSTRACT FROM AUTHOR]

Published
2020
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48. Facile in situpreparation of biologically active multivalent glyconanoparticlesElectronic supplementary information (ESI) available: Synthetic procedures and characterisation data, polymerisation kinetics and UV-vis spectra of nanoparticles. See DOI: 10.1039/b608383h

Author

Spain, Sebastian G., AlbertinPresent address: Joint Research Unit CNRS-bioMérieux, Luca, Lyon, Ecole Normale Supérieure de, a, 46, and Cameron, Neil R.

Abstract

Biologically active multivalent glyconanoparticles are prepared in an extremely simple method by reduction of well-defined glycopolymers, prepared by RAFT polymerisation, in an aqueous solution of HAuCl4.

Published
2006
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49. Alkyl-modified oligonucleotides as intercalating vehicles for doxorubicin uptake via albumin binding

Author

Purdie, Laura, Alexander, Cameron, Spain, Sebastian G., Magnusson, Johannes P., Purdie, Laura, Alexander, Cameron, Spain, Sebastian G., and Magnusson, Johannes P.

Abstract

DNA-based drug delivery vehicles have displayed promise for the delivery of intercalating drugs. Here, we demonstrate that oligonucleotides modified with an alkyl chain can bind to human serum albumin, mimicking the natural binding of fatty acids. These alkyl-DNA-albumin complexes display excellent serum stability and are capable of strongly binding doxorubicin. Complexes are internalized by cells in vitro, trafficking to the mitochondria, and are capable of delivering doxorubicin with excellent efficiency resulting in cell death. However, the cellular localization of the delivered doxorubicin, and ultimately the complex efficacy, is dependent on the nature of the linker between the alkyl group and the oligonucleotide.

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50. Control of aggregation temperatures in mixed and blended cytocompatible thermoresponsive block co-polymer nanoparticles

Author

Foralosso, Ruggero, Moir, Lee, Mastrotto, Francesca, Sasso, Luana, Tchoryk, Aleksandra, Abouselo, Amjad, Grabowska, Anna M., Ashford, Marianne B., Aylott, Jonathan W., Gellert, Paul R., Spain, Sebastian G., Alexander, Cameron, Foralosso, Ruggero, Moir, Lee, Mastrotto, Francesca, Sasso, Luana, Tchoryk, Aleksandra, Abouselo, Amjad, Grabowska, Anna M., Ashford, Marianne B., Aylott, Jonathan W., Gellert, Paul R., Spain, Sebastian G., and Alexander, Cameron

Abstract

A small library of thermoresponsive amphiphilic copolymers based on polylactide-block-poly((2-(2-methoxyethoxy)ethyl methacrylate)-co-(oligoethylene glycol methacrylate)) (PLA-b-P(DEGMA)-co-(OEGMA)), was synthesised by copper-mediated controlled radical polymerisation (CRP) with increasing ratios of OEGMA:DEGMA. These polymers were combined in two ways to form nanoparticles with controllable thermal transition temperatures as measured by particle aggregation. The first technique involved the blending of two (PLA-b-P(DEGMA)-co-(OEGMA)) polymers together prior to assembling NPs. The second method involved mixing pre-formed nanoparticles of single (PLA-b-P(DEGMA)-co-(OEGMA)) polymers. The observed critical aggregation temperature Tt did not change in a linear relationship with the ratios of each copolymer either in the nanoparticles blended from different copolymers or in the mitures of pre-formed nanoparticles. However, where co-polymer mixtures were based on (OEG)9MA ratios within 5-10 mole% , a linear relationship between (OEG)9MA composition in the blends and Tt was obtained. The data suggest that OEGMA-based copolymers are tunable over a wide temperature range given suitable co-monomer content in the linear polymers or nanoparticles. Moreover, the thermal transitions of the nanoparticles were reversible and repeatable, with the cloud point curves being essentially invariant across at least three heating and cooling cycles, and a selected nanoparticle formulation was found to be readily endocytosed in representative cancer cells and fibroblasts.

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