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Cationic Dendritic Polymers and Their Hybridization with Cellulose Nanofibrils
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Fibre- and Polymer Technology, Coating Technology. KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Centres, Wallenberg Wood Science Center. (Michael Malkoch)ORCID iD: 0000-0001-9747-7806
2023 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Antimicrobial resistance (AMR) is one of the major global threats to thehealth of humans, animals, plants and ecosystems. AMR arises whenbacteria, viruses, fungi, and parasites undergo changes over time; makingmedicines such as antibiotics, antivirals, antifungals and antiparasiticineffective at treating infections. In 2014, it caused approximately 700 000deaths worldwide which increased to 1.27 million deaths in 2019.Consequently, there is a need to explore novel technologies andtreatments. Within the development of alternatives to conventional smallmoleculeantibiotics, polycationic macromolecules have emerged, such asdendritic polymers and their nanomaterials.Dendrimers are high precision, branched macromolecules with a highdensity of terminal functional groups. Their unique architecture and abilityfor precise control over both shape and surface functionality make themsuitable for biomedical applications such as drug delivery, gene deliveryand antimicrobials.Cellulose nanofibrils (CNFs) are nanoscale fibrils of cellulose, an abundantpolymer typically derived from wood. The prolonged reliance on fossilbasedproducts is associated with a wide range of adverse environmentalconsequences which have prompted the exploration of raw materialsderived from renewable resources. The intriguing properties of CNFs, suchas high elastic moduli and low densities, have made them attractive asstructural materials from sustainable sources that can form 3D networks.The combination of cationic dendritic polymers and cellulose nanofibrils isexplored in this thesis and presents an exciting avenue for the developmentof innovative biomaterials with antibacterial properties andbiocompatibility. Part of the work focuses on the synthesis of cationicdendritic polymers, with varying types of cationic groups at the peripheralthrough the use of fluoride-promoted esterification chemistry and thioleneclick reactions. Another part focuses on creating crosslinked hybridhydrogels using cationic dendrimers and anionic CNFs. Finally, a part ofthe thesis presents the preparation of hydrogels consisting of dendriticlinear-dendritic (DLD) polymer solutions and anionic CNFs. Overall, thefindings showcase the versatility and promise of the developed cationicdendritic polymers and CNF-based hydrogels against Escherichia coli,Pseudomonas aeruginosa and Staphylococcus aureus bacterial strainswhilst exhibiting low cytotoxicity.

Abstract [sv]

Antimikrobiell resistens (AMR) är ett av dem stora globala hoten motmänniskors, djurs, växters och ekosystemens hälsa. AMR uppstår närbakterier, virus, svampar och parasiter genomgår förändringar över tid,vilket gör läkemedel som antibiotika, antivirala, svampdödande ochantiparasitära medel ineffektiva vid behandling av infektioner. År 2014orsakade AMR ungefär 700 000 dödsfall över hela världen och siffranökade till 1,27 miljoner under 2019. Därför finns det ett behov av attutforska nya teknologier och behandlingar. Inom utvecklingen avalternativ till konventionella småmolekylära antibiotika harpolykatjoniska makromolekyler såsom dendritiska polymerer framträtt.Dendrimerer är kraftigt förgrenade makromolekyler och perfektdefinierade med en hög densitet av funktionella grupper. Deras unikaarkitektur gör dem intressanta för biomedicinska applikationer somfrisättning av läkemedel och antimikrobiella material.Cellulosa nanofibriller (CNF) är fibriller av cellulosa med en diameter inanoskala, en polymer som vanligtvis utvinns från trä. Det långvarigaberoendet av fossilbaserade produkter har resulterat i allvarligamiljökonsekvenser, vilket har drivit på utvecklingen av materialproducerade från förnyelsebara råvaror. CNF har fascinerande egenskapersom hög elasticitetsmodul och låga densiteter, vilket har gjort demattraktiva som strukturella material från hållbara källor som kan bilda 3Dnätverk.Kombinationen av katjoniska dendritiska polymerer och cellulosananofibriller utforskas i detta arbete och presenterar en spännandeutveckling av innovativa biomaterial som är antibakteriella ochbiokompatibla. En del av arbetet är fokuserad på syntesen av katjoniskadendritiska polymerer med varierande typer av katjoniska funktionalitetpå ytan genom att använda esterifieringsreaktioner som katalyseras avcesiumfluorid och därefter tiol-en-klickreaktioner. En annan del ärfokuserad på att skapa hybridhydrogeler som består av katjoniskadendritiska polymerer och anjoniska CNF. Vidare undersöktes hydrogelerbestående av dendritiska-linjära-dendritiska (DLD) polymerer ochanjoniska CNF. Sammanfattningsvis påvisade resultaten mångsidighetenoch potentialen hos dem utvecklade katjoniska dendritiska polymerernaoch CNF-baserade hydrogelerna mot bakteriestammar som Escherichiacoli, Pseudomonas aeruginosa och Staphylococcus aureus, samtidigt somde visade låg cytotoxicitet.

Place, publisher, year, edition, pages
Stockholm, Sweden: KTH Royal Institute of Technology , 2023. , p. 66
Series
TRITA-CBH-FOU ; 2023:33
Keywords [en]
Dendritic polymers; antibacterial materials; carboxylated cellulose nanofibrils; hybrid hydrogels; bis-MPA polyester dendrimers; dendritic linear dendritic
National Category
Materials Chemistry Organic Chemistry Polymer Chemistry Paper, Pulp and Fiber Technology
Research subject
Fibre and Polymer Science
Identifiers
URN: urn:nbn:se:kth:diva-334404ISBN: 978-91-8040-643-7 (print)OAI: oai:DiVA.org:kth-334404DiVA, id: diva2:1789379
Public defence
2023-09-15, F3, Lindstedtsvägen 26 & 28, Stockholm, 09:00 (English)
Opponent
Supervisors
Funder
Knut and Alice Wallenberg Foundation
Note

QC 2023-08-21

Embargo godkänt av skolchef Amelie Eriksson Karlström via e-post 2023-08-22.

Available from: 2023-08-21 Created: 2023-08-18 Last updated: 2024-08-21Bibliographically approved
List of papers
1. Self-Assembled Polyester Dendrimer/Cellulose Nanofibril Hydrogels with Extraordinary Antibacterial Activity
Open this publication in new window or tab >>Self-Assembled Polyester Dendrimer/Cellulose Nanofibril Hydrogels with Extraordinary Antibacterial Activity
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2020 (English)In: Pharmaceutics, E-ISSN 1999-4923, Vol. 12, no 12, article id 1139Article in journal (Refereed) Published
Abstract [en]

Cationic dendrimers are intriguing materials that can be used as antibacterial materials; however, they display significant cytotoxicity towards diverse cell lines at high generations or high doses, which limits their applications in biomedical fields. In order to decrease the cytotoxicity, a series of biocompatible hybrid hydrogels based on cationic dendrimers and carboxylated cellulose nanofibrils were easily synthesized by non-covalent self-assembly under physiological conditions without external stimuli. The cationic dendrimers from generation 2 (G2) to generation 4 (G4) based on trimethylolpronane (TMP) and 2,2-bis (methylol)propionic acid (bis-MPA) were synthesized through fluoride promoted esterification chemistry (FPE chemistry). FTIR was used to show the presence of the cationic dendrimers within the hybrid hydrogels, and the distribution of the cationic dendrimers was even verified using elemental analysis of nitrogen content. The hybrid hydrogels formed from G3 and G4 showed 100% killing efficiency towards Escherichia coli (E. coli), Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa) with bacterial concentrations ranging from 10(5) CFU/mL to 10(7) CFU/mL. Remarkably, the hybrid hydrogels also showed good biocompatibility most probably due to the incorporation of the biocompatible CNFs that slowed down the release of the cationic dendrimers from the hybrid hydrogels, hence showing great promise as an antibacterial material for biomedical applications.

Place, publisher, year, edition, pages
MDPI, 2020
Keywords
cationic dendrimer, antibacterial materials, carboxylated cellulose nanofibrils, hybrid hydrogels
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-289013 (URN)10.3390/pharmaceutics12121139 (DOI)000602524100001 ()33255607 (PubMedID)2-s2.0-85096697401 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation
Note

QC 20210125

Available from: 2021-01-25 Created: 2021-01-25 Last updated: 2024-07-04Bibliographically approved
2. Synthesis and Characterization of Amino-Functional Polyester Dendrimers Based On Bis-MPA with Enhanced Hydrolytic Stability and Inherent Antibacterial Properties
Open this publication in new window or tab >>Synthesis and Characterization of Amino-Functional Polyester Dendrimers Based On Bis-MPA with Enhanced Hydrolytic Stability and Inherent Antibacterial Properties
2023 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 24, no 2, p. 858-867Article in journal (Refereed) Published
Abstract [en]

Polyester dendrimers based on 2,2 bis(hydroxymethyl)propionic acid have been reported to be degradable, non-toxic, and exhibit good antimicrobial activity when decorated with cationic charges. However, these systems exhibit rapid depolymerization, from the outer layer inwards in physiological neutral pHs, which potentially restricts their use in biomedical applications. In this study, we present a new generation of amine functional bis-MPA polyester dendrimers with increased hydrolytic stability as well as antibacterial activity for Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa) planktonic bacteria strains. These new derivatives show generally good cytocompatibility for the concentrations they are active toward bacteria, in monocyte/macrophage-like cells (Raw 264.7), and human dermal fibroblasts. Fluoride - promoted esterification chemistry, anhydride chemistry, and click reactions were utilized to produce a library from generations 1–3 and with cationic peripheral groups ranging from 6 to 24 groups, respectively. The dendrimers were successfully purified using conventional purification techniques as well as characterized by matrix-assisted laser desorption ionization time-of-flight mass spectroscopy, nuclear magnetic resonance, and size exclusion chromatography. As proof of synthetic versatility, dendritic-linear-dendritic block copolymer were successfully synthesized to display cysteamine peripheral functionalities as well as the scaffolding ability with biomedically relevant lipoic acid and methoxy polyethylene glycol.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2023
Keywords
Dendrimer, bis-MPA, hydrolytic stability, antibacterial properties, cytotoxicity, structural diversity, post-functionalization
National Category
Polymer Chemistry Paper, Pulp and Fiber Technology Bio Materials
Research subject
Chemistry
Identifiers
urn:nbn:se:kth:diva-327336 (URN)10.1021/acs.biomac.2c01286 (DOI)000924403000001 ()36689269 (PubMedID)2-s2.0-85147168206 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2017.0300Knut and Alice Wallenberg Foundation, 2018.0452Knut and Alice Wallenberg Foundation, 2019.0002
Note

QC 20230526

Available from: 2023-05-24 Created: 2023-05-24 Last updated: 2023-08-18Bibliographically approved
3. High Water Content Physically Crosslinked Hybrid Hydrogels Based on Polyester Dendrimers and Cellulose Nanofibrils: a Comprehensive Study
Open this publication in new window or tab >>High Water Content Physically Crosslinked Hybrid Hydrogels Based on Polyester Dendrimers and Cellulose Nanofibrils: a Comprehensive Study
(English)Manuscript (preprint) (Other academic)
National Category
Polymer Chemistry Materials Chemistry
Identifiers
urn:nbn:se:kth:diva-334399 (URN)
Note

QC 20230825

Available from: 2023-08-18 Created: 2023-08-18 Last updated: 2023-08-25Bibliographically approved
4. Cellulose Nanofibril Hydrogels Prepared with Dendritic-Linear-Dendritic Block Copolymers
Open this publication in new window or tab >>Cellulose Nanofibril Hydrogels Prepared with Dendritic-Linear-Dendritic Block Copolymers
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(English)Manuscript (preprint) (Other academic)
National Category
Materials Chemistry Paper, Pulp and Fiber Technology
Identifiers
urn:nbn:se:kth:diva-334401 (URN)
Note

QC 20230825

Available from: 2023-08-18 Created: 2023-08-18 Last updated: 2023-08-25Bibliographically approved

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