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Therapeutic Nanocarriers via Cholesterol Directed Self-Assembly of Well-Defined Linear-Dendritic Polymeric Amphiphiles
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Coating Technology.
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Coating Technology.
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2017 (English)In: Chemistry of Materials, ISSN 0897-4756, E-ISSN 1520-5002, Vol. 29, no 9, p. 3891-3898Article 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. Vol. 29, no 9, p. 3891-3898
National Category
Materials Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-208822DOI: 10.1021/acs.chemmater.6b05095ISI: 000401221700009Scopus ID: 2-s2.0-85019081687OAI: oai:DiVA.org:kth-208822DiVA, id: diva2:1108789
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
In thesis
1. Exploring bis-MPA Based Dendritic Structures in Biomedicine
Open this publication in new window or tab >>Exploring bis-MPA Based Dendritic Structures in Biomedicine
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. p. 71
Series
TRITA-CHE-Report, ISSN 1654-1081 ; 2017:33
Keyword
Dendrimers, Polymers, antibacterial, self-assembly
National Category
Polymer Chemistry
Research subject
Chemistry
Identifiers
urn:nbn:se:kth:diva-218161 (URN)978-91-7729-609-6 (ISBN)
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

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