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Exploring Amphiphilic PEGMA-Based Architectures as Nanoparticles for Drug Delivery
KTH, School of Chemical Science and Engineering (CHE), Fibre and Polymer Technology, Coating Technology.ORCID iD: 0000-0001-9035-4547
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Within the last decades, the stated potential of polymer constructs as drug delivery systems have challenged researchers to develop sophisticated polymers with tunable properties. The versatility of polymers makes them highly attractive to tailor nanoparticles (NPs) which fulfill the demands of effective drug delivery systems (DDS). The aim of this work was to design and synthesize amphiphilic ethylene glycol methacrylate-based (EGMA) macromolecules, and explore their potential as NPs for drug delivery.

Initially, a study of the controlled synthesis and solution properties of linear EGMA polymers, as well as the potential to transfer their behavior to amphiphilic comb copolymers, was conducted. Well-controlled polymers with interesting tunable thermo-responsive properties were accomplished by altering the monomer feed ratio. Furthermore, the comb copolymers formed self-assembled core-shell type structures in aqueous solution.

A library of amphiphilic fluorinated polymers was successfully established to explore the potential of EGMA-based polymers in a dual-functional theranostic delivery system. The non-toxic polymers self-assembled into small “stealthy” NPs, and the combination of fluorinated segments with EGMA segments allowed for detection by 19F-MRI with good imaging properties. The hydrophobic core of the NPs was capable to encapsulate and release an anti-cancer therapeutic, and effectively reduced the viability of three different cancer cell lines. The diffusion-controlled release kinetics of the drug from the NPs interestingly depended on the nature of the core moiety.

To reduce issues with instability of self-assembling NP systems the possibility to synthesize amphiphilic hyperbranched dendritic-linear polymers (HBDLPs) was investigated. Their three-dimensional structure was hypothesized to facilitate stabilization as unimolecular micelles. The architecture, hydrophilic/hydrophobic ratio, and high molecular weight showed to be crucial to avoid polymer association and stabilize the HBDLPs individually. In addition, the hyperbranched core of the HBDLPs was readily functionalized with disulfide bonds, either in the backbone or in the pendant groups. Under reductive conditions, selective cleavage of the disulfides thereby enabled either significant molecular weight reduction, or allowed for triggered release of a covalently bound dye, mimicking a drug. Potentially, such HBDLPs could be stable during circulation, while allowing for selective degradation and/or therapeutic release upon delivery to a cancer tissue.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2015. , 69 p.
Series
TRITA-CHE-Report, ISSN 1654-1081 ; 2015:32
National Category
Polymer Technologies
Research subject
Chemical Engineering
Identifiers
URN: urn:nbn:se:kth:diva-173242ISBN: 978-91-7595-630-5 (print)OAI: oai:DiVA.org:kth-173242DiVA: diva2:852263
Public defence
2015-10-02, F3, Lindstedtsvägen 26, KTH, Stockholm, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council
Note

QC 20150909

Available from: 2015-09-09 Created: 2015-09-08 Last updated: 2015-09-09Bibliographically approved
List of papers
1. Thermo-responsive cellulose-based architectures: tailoring LCST using poly(ethylene glycol) methacrylates
Open this publication in new window or tab >>Thermo-responsive cellulose-based architectures: tailoring LCST using poly(ethylene glycol) methacrylates
2011 (English)In: POLYMER CHEMISTRY, ISSN 1759-9954, Vol. 2, no 5, 1114-1123 p.Article in journal (Refereed) Published
Abstract [en]

There is a growing interest in designing advanced macromolecular architectures applicable for instance in drug delivery systems. Employing cellulose in these systems is particularly favorable due to attractive properties such as biocompatibility and low price. Additionally, thermo-responsive polymers of poly(ethylene glycol) methacrylates are promising in this field owing to their biocompatibility and non-toxicity. In the present study, amphiphilic thermo-responsive homo- and copolymers of oligo(ethylene glycol) methyl ether methacrylate (OEGMA(300)) and di(ethylene glycol) methyl ether methacrylate (DEGMA) were synthesized via ARGET ATRP. Both linear copolymers of DEGMA/OEGMA(300) as well as comb architectures with copolymers of DEGMA/OEGMA(300) grafted from hydroxypropyl cellulose were produced. The lower critical solution temperature of the linear copolymers was readily tailored by altering the monomer feed ratio. The grafting of the thermo-responsive polymers from hydroxypropyl cellulose resulted in a consistent decrease of the lower critical solution temperature compared to the linear analogues; however, interestingly the ability to tune the transition temperature remained. Moreover, the amphiphilic comb architectures formed polymeric micelles with low critical micelle concentrations. Consequently, these advanced architectures combine the favorable properties of hydroxypropyl cellulose with the interesting thermo-responsive and stealth properties of poly(ethylene glycol) methacrylates, and may, therefore, find potential applications in biomedicine.

National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-34355 (URN)10.1039/c0py00417k (DOI)000290681800015 ()2-s2.0-79955864168 (Scopus ID)
Funder
Swedish Research Council
Note
QC 20110818Available from: 2011-08-18 Created: 2011-06-07 Last updated: 2015-09-09Bibliographically approved
2. In Vitro Evaluation of Non-Protein Adsorbing Breast Cancer Theranostics Based on 19F-Polymer Containing Nanoparticles
Open this publication in new window or tab >>In Vitro Evaluation of Non-Protein Adsorbing Breast Cancer Theranostics Based on 19F-Polymer Containing Nanoparticles
Show others...
2013 (English)In: Particle & particle systems characterization, ISSN 0934-0866, E-ISSN 1521-4117, Vol. 30, no 4, 381-390 p.Article in journal (Refereed) Published
Abstract [en]

Eight fluorinated nanoparticles (NPs) are synthesized, loaded with doxorubicin (DOX), and evaluated as theranostic delivery platforms to breast cancer cells. The multifunctional NPs are formed by self-assembly of either linear or star-shaped amphiphilic block copolymers, with fluorinated segments incorporated in the hydrophilic corona of the carrier. The sizes of the NPs confirm that small circular NPs are formed. The release kinetics data of the particles reveals clear hydrophobic core dependence, with longer sustained release from particles with larger hydrophobic cores, suggesting that the DOX release from these carriers can be tailored. Viability assays and flow cytometry evaluation of the ratios of apoptosis/necrosis indicate that the materials are non-toxic to breast cancer cells before DOX loading; however, they are very efficient, similar to free DOX, at killing cancer cells after drug encapsulation. Both flow cytometry and confocal microscopy confirm the cellular uptake of NPs and DOX-NPs into breast cancer cells, and in vitro 19F-MRI measurement shows that the fluorinated NPs have strong imaging signals, qualifying them as a potential in vivo contrast agent for 19F-MRI.

Keyword
polymers, theranostic nanoparticles, drug delivery, doxorubicin, breast cancer
National Category
Other Chemistry Topics
Identifiers
urn:nbn:se:kth:diva-123125 (URN)10.1002/ppsc.201300018 (DOI)000318106000012 ()2-s2.0-84876724571 (Scopus ID)
Funder
Swedish Research Council, 2011-3720 2009-3259Vinnova
Note

QC 20130604

Available from: 2013-06-04 Created: 2013-06-03 Last updated: 2017-12-06Bibliographically approved
3. Toward Unimolecular Micelles with Tunable Dimensions Using Hyperbranched Dendritic-Linear Polymers
Open this publication in new window or tab >>Toward Unimolecular Micelles with Tunable Dimensions Using Hyperbranched Dendritic-Linear Polymers
Show others...
2014 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 15, no 6, 2235-2245 p.Article in journal (Refereed) Published
Abstract [en]

A library of amphiphilic, hyperbranched dendritic-linear polymers (HBDLPs) are successfully synthesized, and evaluated as potential unimolecular micelles. Hyperbranched macroinitiators (HBMI), extended with poly(ethylene glycol) methacrylate (P(OEGMA)), are afforded via a combination of self-condensing vinyl (co)polymerization (SCV(C)P) and atom transfer radical polymerization (ATRP), providing a versatile two-step synthetic route. The HBDLP architecture and chain lengths are varied, and the effect on the nanoparticle (NP) stability and properties are evaluated. The HBDLPs form predominantly stable and spherical NPs, and the NP dimensions could be tailored by the HBDLP characteristics. The NPs formed are of high molecular weight, and their stability varies with the properties of the corresponding HBDLP. Too small dendritic segment, or too low degree of PEGylation, results to some extent in NP aggregation, while higher molecular weight HBDLPs, with a high amount of hydrophilic segments, appears to form discrete unimolecular micelles. The versatility of the platform is further demonstrated by the convenience of forming a HBDLP. with a more complex, linear copolymer extension instead of P(OEGMA).

Keyword
Condensing Vinyl Polymerization, Living Radical Polymerization, Block-Copolymer Hybrids, AB-Asterisk Monomers, Breast-Cancer Cells, In-Vitro Evaluation, Drug-Delivery, Biological Applications, Star Polymers, Nanoparticles
National Category
Other Chemistry Topics
Identifiers
urn:nbn:se:kth:diva-148228 (URN)10.1021/bm5003637 (DOI)000337497100031 ()2-s2.0-84902158485 (Scopus ID)
Funder
Swedish Research Council, 2011-3720 2009-3259
Note

QC 20140805

Available from: 2014-08-05 Created: 2014-08-04 Last updated: 2017-12-05Bibliographically approved
4. Disulfide-Functionalized Unimolecular Micelles as Selective Redox-Responsive Nanocarriers
Open this publication in new window or tab >>Disulfide-Functionalized Unimolecular Micelles as Selective Redox-Responsive Nanocarriers
Show others...
2015 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602Article in journal (Refereed) Epub ahead of print
Abstract [en]

Redox-sensitive hyperbranched dendritic-linear polymers (HBDLPs) were prepared and stabilized individually as unimolecular micelles with diameters in the range 25–40 nm. The high molecular weight (500–950 kDa), core–shell amphiphilic structures were synthesized through a combination of self-condensing vinyl copolymerization (SCVCP) and atom transfer radical polymerization (ATRP). Cleavable disulfide bonds were introduced, either in the backbone, or in pendant groups, of the hyperbranched core of the HBDLPs. By triggered reductive degradation, the HBDLPs showed up to a 7-fold decrease in molecular weight, and the extent of degradation was tuned by the amount of incorporated disulfides. The HBDLP with pendant disulfide-linked functionalities in the hyperbranched core was readily postfunctionalized with a hydrophobic dye, as a mimic for a drug. An instant release of the dye was observed as a response to a reductive environment similar to the one present intracellularly. The proposed strategy shows a facile route to highly stable unimolecular micelles, which attractively exhibit redox-responsive degradation and cargo release properties.

National Category
Polymer Chemistry
Identifiers
urn:nbn:se:kth:diva-173310 (URN)10.1021/acs.biomac.5b00809 (DOI)
Note

QP 201509

Available from: 2015-09-09 Created: 2015-09-09 Last updated: 2017-12-04Bibliographically approved

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