Hyperbranched Polydendrons: A New Macromolecular Architecture PDF
Preview Hyperbranched Polydendrons: A New Macromolecular Architecture
Springer Theses Recognizing Outstanding Ph.D. Research Fiona L. Hatton Hyperbranched Polydendrons A New Macromolecular Architecture Springer Theses Recognizing Outstanding Ph.D. Research Aims and Scope The series “Springer Theses” brings together a selection of the very best Ph.D. theses from around the world and across the physical sciences. Nominated and endorsed by two recognized specialists, each published volume has been selected foritsscientificexcellenceandthehighimpactofitscontentsforthepertinentfield of research. For greater accessibility to non-specialists, the published versions includeanextendedintroduction,aswell asaforewordbythestudent's supervisor explainingthespecialrelevanceoftheworkforthefield.Asawhole,theserieswill provide a valuable resource both for newcomers to the research fields described, and for other scientists seeking detailed background information on special questions. Finally, it provides an accredited documentation of the valuable contributions made by today's younger generation of scientists. Theses are accepted into the series by invited nomination only and must fulfill all of the following criteria (cid:129) They must be written in good English. (cid:129) The topic should fall within the confines of Chemistry, Physics, Earth Sciences, Engineering and related interdisciplinary fields such as Materials, Nanoscience, Chemical Engineering, Complex Systems and Biophysics. (cid:129) The work reported in the thesis must represent a significant scientific advance. (cid:129) Ifthethesisincludespreviouslypublishedmaterial,permissiontoreproducethis must be gained from the respective copyright holder. (cid:129) They must have been examined and passed during the 12 months prior to nomination. (cid:129) Each thesis should include a foreword by the supervisor outlining the signifi- cance of its content. (cid:129) The theses should have a clearly defined structure including an introduction accessible to scientists not expert in that particular field. More information about this series at http://www.springer.com/series/8790 Fiona L. Hatton Hyperbranched Polydendrons A New Macromolecular Architecture Doctoral Thesis accepted by the University of Liverpool, UK 123 Author Supervisor Dr. FionaL. Hatton Prof. SteveRannard FibreandPolymer Technology Department ofChemistry KTH RoyalInstitute of Technology University of Liverpool Stockholm Liverpool Sweden UK ISSN 2190-5053 ISSN 2190-5061 (electronic) SpringerTheses ISBN978-3-319-18752-5 ISBN978-3-319-18753-2 (eBook) DOI 10.1007/978-3-319-18753-2 LibraryofCongressControlNumber:2015939159 SpringerChamHeidelbergNewYorkDordrechtLondon ©SpringerInternationalPublishingSwitzerland2015 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpart of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission orinformationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilar methodologynowknownorhereafterdeveloped. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfrom therelevantprotectivelawsandregulationsandthereforefreeforgeneraluse. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authorsortheeditorsgiveawarranty,expressorimplied,withrespecttothematerialcontainedhereinor foranyerrorsoromissionsthatmayhavebeenmade. Printedonacid-freepaper SpringerInternationalPublishingAGSwitzerlandispartofSpringerScience+BusinessMedia (www.springer.com) Part of this thesis have been published in the following journal articles: Fiona L. Hatton, Tom O. McDonald, Pierre Chambon, Andrew Owen, Steve P. Rannard, “Hyperbranched polydendrons: a new controlled macromolecular architecture with self-assembly in water and organic solvents”, Chem. Sci., 2014, 5, 1844–1853. Fiona L. Hatton, Lee M. Tatham, Louise R. Tidbury, Pierre Chambon, Tao He, Andrew Owen and Steve P. Rannard, “Hyperbranched polydendrons: a new nanomaterials platform with tuneable permeation through model gut epithelium”, Chem. Sci., 2015, 6, 326–334. ’ Supervisor s Foreword Over the past three decades, polymer chemistry has seen the development of new conceptsandexperimentaltechniquesthathavebeenincreasinglyapproachablefor research groups without access to highly specialised equipment. The advent of highly and ideally branched polymer architectures in the form of hyperbranched polymers and dendrimers heralded a new era for polymer science. Almost con- currently, the introduction of controlled radical polymerisation allowed research groups across the world to develop new chemical strategies towards the formation of ever more complex polymers with placement of functionality, defined chain lengths and tuning of physical properties. At the overlap of dendrimers and controlled radical polymerisation, a range of polymerstermed“linear-dendritichybrids”havegrownininterestandscope.These materials attempt to benefit from both chemistries by taking dendrons, the smaller buildingblocksofdendrimers,andusingthemtoadornlinearpolymerseitheratthe chain ends or as pendant units. In some cases, dendrons have become the linking sections for novel star polymers whilst in other elegant syntheses, dendrons of different chemical types have been linked together to make macromolecules that possess multiple peripherally-initiated linear polymers and numerous functional groups. This control of architecture comes at some synthetic cost to the chemist. Elaborate strategies to generate uniform macromolecules with defined complexity may also require a large number of chemical stages, each requiring different con- ditions and purification. The result may be low yielding reactions and, therefore, a subsequent reduction in the breadth of viable application. The researchoutlined in thisthesishas introduced completelynew structuresto the field of complex macromolecular architectures. By combining low generation dendrons with controlled radical polymerisation and the concepts from branched vinyl polymerisation, the one-pot synthesis of “hyperbranched-polydendrons” has beenachieved.Inessence,thesematerialsarelinear-dendritichybridpolymersthat are joined along the linear polymer chain to incorporate tens, and sometimes hundreds, of chains on average, each one with a dendron at one chain-end. To vii viii Supervisor’sForeword achievethesestructures,alevelofnon-uniformityhasbeenacceptedandnon-ideal distributions of architecture and molecular weight are present; however, the hyperbranched-polydendrons reported here have been shown to undergo nanopre- cipitation to form extremely uniform self-assembled structures whilst requiring relatively simple synthetic strategies and providing a high degree of structural and chemical manipulation. The importance of such chemistry may not yet be completely clear. Here, the ability of hyperbranched-polydendrons to encapsulate poorly-soluble compounds, and the opportunity to vary the surface functionality and internal environment of their nanoprecipitates, has been utilised in an exploration of their potential in nanomedicine. The role of particulate medicines is growing rapidly and clinics across the world regularly dose nanomedicines for a range of diseases. Administration of nanomedicines to result in circulating nanoparticles is only currentlypossiblethroughintravenousinjection,however,nanoprecipitatesderived from hyperbranched-polydendrons have shown some indication that permeation through the gut may be possible if the surface chemistry is accurately controlled. Thisisuniquelypossiblethroughthesynthesisofthisnewmaterialtypeandfuture researchers will be presented with opportunities that have been too complex to derive through previous strategies. It may be that nanomedicine isnot the ultimate bestapplicationofhyperbranched-polydendronsbutthisthesisopensthedoorfora wealthofpotentialapplicationinvestigations,asearlyreportsofdendrimers,linear- dendritic-hybrids and controlled radical polymerisation all individually did in the past. Liverpool, UK Prof. Steve Rannard February 2015 Abstract A novel architecture ‘hyperbranched polydendrons’ (hyp-polydendrons) was pro- duced via the synthesis of low generation dendron initiators for ATRP and sub- sequent copolymerisation of vinyl and divinyl monomers, to give large polymeric macromolecules containing dendron moieties at the end of each primary chain. Subsequentstudiesofsuchmaterialswereperformedtoassesstheirabilitytoform nanoparticles via a nanoprecipitation approach, utilising organic solvent and aqueous nanoparticle formation. It was found that the branched polymers were superior to the linear polymer analogues when assessing their nanoprecipitation behaviour. Mixed initiator hyp-polydendrons were also synthesised by the statistical incorporation of different functionality initiators into the reaction mixture. Here, a G2dendronanddifferentPEGmacroinitiatorsweremixedstatisticallytoproducea seriesofmaterialswheretheprimarychainlengthofthemonomerHPMAwasalso varied. This led to a series of nanoparticles which showed a variation of internal environments when studied using different fluorescent dyes (Nile red and pyrene). Initial pharmacological experiments were promising, however, the initial set of materials did not show prolonged stability in physiologically relevant conditions when using a short PEG macroinitiator (750PEG). Extending the length of the PEG chain (2000PEG initiator) in the mixed poly- merisations produced a range of materials with varying solubilities and, therefore, nanoprecipitation behaviour. Nanoparticles were formed which were stable under physiologically relevant conditions and were studied for their cytotoxicity and transcellular permeability in Caco-2 cells. These materials showed limited toxicity at the concentrations studied and enhanced permeation though the Caco-2 cell monolayer, which is a model of the intestinal epithelial cells. Furtherstudiesofthenanoprecipitationbehaviour ofdifferent molecularweight fractions of the hyp-polydendrons were conducted. This involved separation of molecular weight fractions by dialysis of the hyp-polydendrons against two dif- ferent good solvents, leading to two HMW fractions and two LMW fractions. Analysis of the nanoprecipitation behaviour of these fractions showed that the HMWfractionsproducedparticleswithmorenarrowPdIs,andthemixingofalow ix x Abstract amount of an HMW fraction (1 wt%) with a linear polymer improved the nano- precipitation behaviour hugely. Encapsulation of two different guest molecules via nanoprecipitation was assessedusingFRET,whichcanreportontheproximityoftwofluorophores.Dual loading of the particles with DiO and DiI in a 1:1 ratio gave particles which exhibitedaFRETsignal,thereforeindicatingthatthetwofluorophoreswerelocated in the same nanoparticle. Somewhat unexpectedly, it was found that upon mixing ofthetwosinglyloadedparticlestheobservedFRETratioincreasedovertimeuntil it reached a similar value obtained within the dual loaded nanoparticles. This was possibly due to nanoparticle–nanoparticle collisions. Therefore, hyp-polydendrons were produced and utilised to form nanoparticles via a nanoprecipitation approach. Loading of the nanoparticles was achieved and pharmacological benefits were observed for some of the nanoparticle samples, suggesting future benefits for these polymer architectures in nanomedicine applications.
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