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Preparation of hyaluronic acid nanoparticles via hydrophobic association assisted chemical cross-linking: an orthogonal modular approach
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
2011 (English)In: Soft Matter, ISSN 1744-683X, E-ISSN 1744-6848, Vol. 7, no 16, 7517-7525 p.Article in journal (Refereed) Published
Abstract [en]

The objective of this study was to develop an efficient and stable drug delivery nanocarrier based on a dually functionalized hyaluronic acid (HA) derivative which could be used as a long circulating drug delivery vehicle. Self-assembled HA nanoparticles (HA NPs) were prepared by attaching pyrene to the HA backbone and the obtained physical NPs were stabilized by chemical cross-linking of the HA chains to form hydrophobic core-hydrophilic shell NPs. Orthogonal chemoselective reactions were applied for conversion of HA into its amphiphilic derivative and subsequent cross-linking of the formed micellar-type associates. Chemical stabilization of the physical HA associates afforded therefore very stable nanoparticles that could easily be re-suspended in aqueous media after freeze-drying. In contrast, freeze-drying of the uncross-linked physically associated particles resulted in a non-soluble material. Doxorubicin (DOX), a typical anticancer drug, was entrapped into HA NPs via ionic and/or hydrophobic interactions and used for in vitro drug release. Higher loading efficiency and the slower release profile of DOX from HA NPs were obtained with the hydrophobically encapsulated drug. We have shown that free HA NPs were readily taken up by NIH 3T3 cells without causing any toxicity to the cells, while the DOX-loaded HA NPs resulted in increased cell death comparable to the free drug. This study clearly showed the applicability of orthogonal chemoselective modifications for the synthesis of stable HA nanogel particles as a potential cancer-targeted drug delivery system.

Place, publisher, year, edition, pages
2011. Vol. 7, no 16, 7517-7525 p.
National Category
Natural Sciences Polymer Chemistry
Research subject
Chemistry with specialization in Polymer Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-158426DOI: 10.1039/c1sm05785eISI: 000293412900049OAI: oai:DiVA.org:uu-158426DiVA: diva2:439546
Available from: 2011-09-08 Created: 2011-09-07 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Multi-functional Hyaluronan Based Biomaterials for Biomedical Applications
Open this publication in new window or tab >>Multi-functional Hyaluronan Based Biomaterials for Biomedical Applications
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis presents strategies for constructing multi-functional biomaterials based on hyaluronan (HA) derivatives for various biomedical applications, such as drug delivery, tissue regeneration, and imaging biomaterials. The aim of this study is to improve the functionalities of HA biomaterials as well as simplify the preparation procedures.  Native HA polymer contains D-glucuronic acid residue with a carboxyl group per disaccharide unit that can be easily modified by carbodiimide-mediated amidation reaction. Therefore, we have designed a series of orthogonal groups (hydrazide, carbazate, aldehyde, and thiol) that can be linked to HA under mild conditions using the carbodiimide chemistry. Multiple functionalities can be introduced to the obtained HA derivatives via chemoselective “click”-type transformations.  

The modified HA derivatives were used for the preparation of either nanogel particles (NPs) or bulk hydrogels. Due to “click” character of the reactions used, structural HA transformations were performed with high fidelity on different scales including molecular (polymers), nanometer (NPs), and a visible scale (bulk hydrogels). By linking pyrene or camptothecin to hydrophilic HA backbone, amphiphilic polymers were obtained and utilized as drug delivery carriers or prodrugs, respectively. Subsequently, physically loaded drug (doxorubicin) could be released upon degradation of HA carriers, while the chemically linked camptothecin was released intact by a thiol-triggered cleavage reaction. Bisphosphonated HA (HA-BP) polymers were prepared to induce hydrogel scaffold bio-mineralization for bone regeneration application. Moreover, we could recruit strong binding capacity of bisphosphonate (BP) groups to calcium ions for the formation of physically crosslinked HA-BP gel upon simple mixing of the polymer and calcium phosphate nanoparticle components. This gel was more stable in vivo compared to hydrazone crosslinked HA gels. Furthermore, the hydrogel composed of fluorine-19 (19F) linked HA polymer was successfully observed by both 1H and 19F MR imaging.        

In conclusion, the presented herein study describes new approaches for building up multi-functional biomaterials from the HA-based blocks. The utilization of carbodiimide and click chemistries along with the enzymatic degradation of HA allowed simple and efficient interconversion between HA macromolecules, nanoparticles and macroscopic hydrogels. These HA-based biomaterials show high potential for use in the fields of drug delivery, bone regeneration, and imaging techniques.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1155
Keyword
hyaluronan, biomaterials functionalizations, biomedical applications, orthogonal chemistry, drug delivery, tissue regeneration, MRI
National Category
Polymer Chemistry Materials Chemistry
Research subject
Chemistry with specialization in Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-224371 (URN)978-91-554-8974-8 (ISBN)
Public defence
2014-09-17, Häggsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2014-06-04 Created: 2014-05-09 Last updated: 2014-06-30

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Yang, XiaKootala, SujitHilborn, JönsOssipov, Dmitri A.

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