Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Exploring bis-MPA Based Dendritic Structures in Biomedicine
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Coating Technology.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the last decades there has been significant advances in polymer chemistry. New coupling chemistries, polymerization techniques and accelerated approaches enable researches to push the limits of structural control. One outcome of such development is the field of linear dendritic (LD) and dendritic linear dendritic (DLD) hybrid materials, drawing benefit from both linear and dendritic material properties. LD-hybrids with their high density of functional groups and customizability offer much promise for use in biological applications. This thesis deals with the potential use of sophisticated LD-hybrid materials focusing on the field of biomedicine and biomedical applications. The linear component is manly poly(ethylene glycol) (PEG) while the dendritic part consists of 2,2-Bis(hydroxymethyl)propionic (bis-MPA) building blocks.

Initially a family of unsymmetrical LD amphiphiles was constructed and evaluated as carriers for drug delivery of chemotherapeutics. Through self-assembly driven by their amphiphilic nature nanocarriers (NC) were constructed with a hydrophobic core and hydrophilic corona. NC were found to enhance the effect of conventional therapeutics by relocating the drug from just the nucleus to the mitochondria among other organelles. Their versatile nature allowed for dual loading of a combination of chemotherapeutics and circumvented the resistance mechanism of resistant cancer cells.

Dendrimers containing a disulfide in the backbone were also constructed, these enabled the selective fragmentation of the dendrimer by reduction to small molecular thiols. The fragments were also envisioned to disrupt the delicate thiol-disulfide balance intracellularly causing reactive oxygen species (ROS). Dendrimers were elaborated by conjugation to linear PEG creating LD-hybrids and evaluated in vitro and where found to cause high degree of ROS in cancerous cells.

Thiol functional polymers were created, including linear polymers, dendrimers and DLD-hybrids. The DLD-hybrids were utilized as hydrogels through two efficient chemistries relying on the versatility of the thiol. By varying the generation of the LD-hybrid and the cross-linking chemistry the modulus could be tuned.

Amine functional LD-hybrids were constructed utilizing the amino acid alanine. Scaffolds were utilized as antimicrobial hydrogels for prophylaxis during surgical intervention. LD-hybrids were initially evaluated in planktonic mode, and were found to have broad spectrum effect and were highly effective against resistant bacteria. Gelation was studied relying on N-hydroxysuccinimide (NHS) esters as cross-linkers, enabling instantaneous gelation under biological conditions. The gels moduli could be varied to match various tissues including stromal and muscle. The effect of the antimicrobial coatings was investigated with promising results both in vitro and in vivo.

Finally, more industrially applicable hyperbranched LD-hybrids were constructed. The synthetic strategy relied on a convenient pseudo one-pot approach using Fisher esterification along with sequential monomer addition. Materials were found to have properties and characteristics similar to those of perfect dendritic LD-hybrids. And the scaffolds were evaluated in a range of applications such as hydrogels and isopourous films with promising results.

Abstract [sv]

Under de senaste decennierna har stora framsteg skett inom polymerkemin. Ny kopplingskemi och polymerisationstekniker har givit forskare möjligheten att ta fram mer kontrollerade polymera strukturer. Ett resultat ur polymerkemins framfart är linjär dendritiska (LD) hybrider som tar fördel av både materialegenskaper från linjära polymerer såväl som dendritiska. Deras struktur och egenskaper är lovande för framtida användningar inom medicinska och biomedicinska applikationer. Den här avhandlingen granskar användningen av LD-hybrider i ett flertal biomedicinska applikationer. Linjär poly(etylenglykol) används som linjär del och den dendritiska strukturen baseras på 2,2-Bis(hydroxymethyl)propionic (bis-MPA).

Inledningsvis så utvärderas osymmetriska LD-hybrider, modifierade för att vara amfifila, som bärare inom drogleverans av cancer droger. Genom ”self–assembly” orsakad av deras amfifila karaktär så bildades nanobärare (NB) med hydrofob insida och hydrofilt yttre skal. NB fanns öka effekten av konventionell kemoterapeutiska droger genom att omlokalisera drogerna från bara cellkärnan till andra organeller, bland annat mitokondrien. NB kunde bära en kombination av cellgifter och kringgå resistansmekanismen av resistenta cancerceller.

Dendrimerer som innehåller en intern disulfidbrygga togs farm. Deras natur möjliggjorde selektiv fragmentering under reduktiva förhållanden. Fragmenten består av lågmolekylare tiol funktionella molekyler med potentiell användning inom ytbehandling. Fragmenten kunde störa cellers balans mellan tiol och disulfide vilket resulterar i reaktiva syreföreningar (RSF). Dendrimererna kunde brytas ner under biologiska förhållanden och skapade ROF i cancerceller.

Tiolfunktionella polymerer framtogs däribland linjära polymerer, dendrimerer och LD-hybrider. LD-hybriderna användes för konstruktion av hydrogeler genom två olika typer av tvärbindnings kemi. Deras modul kunde varieras genom att variera dendristisk generation och tvärbindningskemi.

Aminfunktionella LD-hybrider framtogs genom användning av aminosyran alanin. Strukturerna användes för att utveckla en ny metod av profylax, en antibakteriell spraybar gel, som ska hindra infektioner associerade med kirurgiska ingrepp. Strukturerna hade bredspektrums effekt , även mot resistenta bakterier. Genom N-hydroxysuccinimide (NHS) ester baserade tvärbindare kunde geler med modul motsvarande från fett upp till broskvävnad skapas under biologiska förhållanden. Gelerna visade god effekt både in vitro och in vivo.

Slutligen, skapades hyperförgrenade LD-hybrider mellan PEG och bis-MPA som ett mer industriellt applicerbart alternativ. Genom enkel kemi med sekventiella additioner av bis-MPA monomer kunde ett span av LD-Hybrider skapas med egenskaper liknande de perfekt dendritiska motparterna.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2017. , 71 p.
Series
TRITA-CHE-Report, ISSN 1654-1081 ; 2017:33
Keyword [en]
Dendrimers, Polymers, antibacterial, self-assembly
National Category
Polymer Chemistry
Research subject
Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-218161ISBN: 978-91-7729-609-6 (print)OAI: oai:DiVA.org:kth-218161DiVA: diva2:1159787
Public defence
2017-12-15, F3, Lindstedtsvägen 26, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 20171124

Available from: 2017-11-24 Created: 2017-11-23 Last updated: 2017-11-24Bibliographically approved
List of papers
1. Therapeutic Nanocarriers via Cholesterol Directed Self-Assembly of Well-Defined Linear-Dendritic Polymeric Amphiphiles
Open this publication in new window or tab >>Therapeutic Nanocarriers via Cholesterol Directed Self-Assembly of Well-Defined Linear-Dendritic Polymeric Amphiphiles
Show others...
2017 (English)In: Chemistry of Materials, ISSN 0897-4756, E-ISSN 1520-5002, Vol. 29, no 9, 3891-3898 p.Article in journal (Refereed) Published
Abstract [en]

A novel platform of fluorescently labeled nanocarriers (NCs) is herein proposed based on amphiphilic linear-dendritic polymeric hybrids. These sophisticated polymers were synthesized with a high degree of structural control at a macro-molecular level, displayed hydrophobic cholesterol compartments as chain-terminus groups of the dendritic block and hydrophilic bifunctional linear poly(ethylene glycol) (PEG) block. Spherical supramolecular assemblies with therapeutically relevant properties were successfully achieved including (i) sizes in the region of 100 to 200 nm; (ii) narrow dispersity profile with values close to 0.12; and (iii) self-assembly down to nanomolar concentrations. The modular nature of the NCs permitted the encapsulation of single or dual anticancer drugs and in parallel provide intracellular fluorescent traceability. As polymer therapeutics, the NCs were proven to penetrate the cancerous cell membranes and deliver the cargo of drugs into the nuclei as well as the cytoplasm and mitochondria. The dual drug delivery of both doxorubicin (DOX) and triptolide substantially enhanced the therapeutic efficacy with a 63% significant increase against resistant breast cancer cells when compared to free DOX.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
National Category
Materials Chemistry
Identifiers
urn:nbn:se:kth:diva-208822 (URN)10.1021/acs.chemmater.6b05095 (DOI)000401221700009 ()2-s2.0-85019081687 (Scopus ID)
Funder
EU, FP7, Seventh Framework ProgrammeKnut and Alice Wallenberg FoundationSwedish Research Council
Note

QC 20170613

Available from: 2017-06-13 Created: 2017-06-13 Last updated: 2017-11-23Bibliographically approved
2. Heterogeneous Rupturing Dendrimers
Open this publication in new window or tab >>Heterogeneous Rupturing Dendrimers
2017 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126Article in journal (Refereed) Published
Abstract [en]

Utilizing macromolecular scaffolds as templates for the production of small molecules that are distinctively different from the original monomer feedstock has many potential applications. Herein, as a proof-of-concept, a family of dendrimers displaying internally queued disulfide bridges were synthesized and exploited as flawless macromolecular templates that selectively rupture into a set of monomeric mercaptans. Disassembly was accomplished in a reducing environment, using DTT as an external stimulus, and the thiol constituents were successfully isolated. Their composition was dictated by three dendritic regions, i.e., (i) the symmetrical trithiol of the core (C3), (ii) the interior-asymmetric trithiols (CD2), and (iii) the periphery-asymmetric monothiols (DB2), in which B functionality is of an orthogonal nature. Taking into account the steady state between disulfides and thiols in all living cells, the collapse of the dendrimers to a multitude of smaller thiols was intracellularly assessed as a means to disrupt the balance of reactive oxygen species (ROS) often elevated in cancer cells. Indeed, the fragmentation induced a significant increase of ROS in human lung carcinoma A549 cells. These findings can potentially alter the perception of dendrimers being limited to carriers to being prodrugs for intracellular delivery of ROS with the potential to fight cancer.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-218107 (URN)10.1021/jacs.7b10377 (DOI)000417669000064 ()2-s2.0-85037526519 (Scopus ID)
Note

QC 20171124

Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2017-12-29Bibliographically approved
3. Facile thiolation of hydroxyl functional polymers
Open this publication in new window or tab >>Facile thiolation of hydroxyl functional polymers
2017 (English)In: Polymer Chemistry, ISSN 1759-9954, E-ISSN 1759-9962, Vol. 8, no 34, 4996-5001 p.Article in journal (Refereed) Published
Abstract [en]

Sulfur is an important component in many biological systems. In the hands of an organic chemist it can provide an ample handle for a myriad of robust reactions including thiol-ene click chemistry. However, in polymer chemistry the thiol functionality is rarely attributed to the macromolecule due to unatainable synthetic protocols. Herein, we provide a simple and robust strategy to produce thiol-functional polymers. The chemistry capitalizes on an unsymmetrical disulfide that straightforwardly converts hydroxyl functional polymers to their thiolated counterpart. Finally, PEG hydrogels, using both thiol-ene and Michael addition, is used to showcase the possibilities presented by thiol functional polymers.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2017
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-218108 (URN)10.1039/C7PY01097D (DOI)000409022200009 ()2-s2.0-85028611940 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, 2012-0196EU, FP7, Seventh Framework Programme, 60418
Note

QC 20171124

Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2017-11-24Bibliographically approved
4. Linear-Dendritic Polyesters as Antimicrobial Hydrogels
Open this publication in new window or tab >>Linear-Dendritic Polyesters as Antimicrobial Hydrogels
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-218160 (URN)
Note

QC 20171124

Available from: 2017-11-23 Created: 2017-11-23 Last updated: 2017-11-24Bibliographically approved
5. Multifunctional Poly(ethylene glycol): Synthesis, Characterization, and Potential Applications of Dendritic-Linear-Dendritic Block Copolymer Hybrids
Open this publication in new window or tab >>Multifunctional Poly(ethylene glycol): Synthesis, Characterization, and Potential Applications of Dendritic-Linear-Dendritic Block Copolymer Hybrids
Show others...
2013 (English)In: Macromolecules, ISSN 0024-9297, E-ISSN 1520-5835, Vol. 46, no 10, 3726-3736 p.Article in journal (Refereed) Published
Abstract [en]

Emerging dendritic-linear-dendritic (DLD) hybrids that possess synergetic properties of linear and highly functional branched dendritic polymers are becoming important macromolecular scaffolds in fields ranging from biomedicine to nanotechnology. By exploiting pseudo-one-step polycondensation reactions, a facile and scalable synthetic methodology for the construction of highly functional DLDs has been developed. A library of three sets of DLDs exhibiting a hydrophilic linear PEG core with covalently attached hyperbranched bis-MPA blocks was synthesized up to the seventh generation with 256 reactive peripheral hydroxyl groups. The degree of branching for the hybrids was found between 0.40 and 0.59 with dispersities ranging from 1.03 to 1.88. The introduction of hyperbranched components resulted in control over or even full disruption of the crystallinity of the PEG. Postfunctionalizations of the peripheral hydroxyl groups with azides, allyls, and ATRP initiators yielded reactive intermediates. These intermediates were successfully assessed through UV-initiated thiol-ene coupling reactions for the synthesis of charged hybrids. ATRP of styrene from the pheriphery afforded amphiphilic macromolecules. Finally, their scaffolding capacity was evaluated for the fabrication of 3D networks, i.e, novel dendritic hydrogels and highly ordered breath figures.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2013
Keyword
Amphiphilic macromolecules, Degree of branching, Macromolecular scaffolds, Peripheral hydroxyl, Polycondensation reactions, Reactive intermediate, Synergetic properties, Synthetic methodology
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-124987 (URN)10.1021/ma4003984 (DOI)000319795800004 ()2-s2.0-84878266827 (Scopus ID)
Funder
Vinnova, 2012-01252Swedish Research Council, 2011-4477 897 2010-453
Note

QC 20130806

Available from: 2013-08-06 Created: 2013-08-02 Last updated: 2017-12-06Bibliographically approved

Open Access in DiVA

The full text will be freely available from 2018-11-24 00:00
Available from 2018-11-24 00:00

Search in DiVA

By author/editor
Andrén, Oliver
By organisation
Coating Technology
Polymer Chemistry

Search outside of DiVA

GoogleGoogle Scholar

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 87 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf