Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • 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
Toxicological and Immunomodulatory Properties of Mesoporous Silica Particles: Applications in Life Sciences
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mesoporous silica particles offer great potential benefits as vehicles for drug delivery and in other biomedical applications. They present a high loading capacity due their ordered and size-tuneable pores that allow molecules to be loaded and released. In addition, they offer the possibility to enhance oral bioavailability of drugs with limited aqueous solubility and to protect pH sensitive drugs from the acidic conditions in the stomach on their way to the intestine.

The aim of this thesis was to evaluate the biocompatibility and effects of mesoporous silica particles on immunocompetent cells. Subsequently, two potential life sciences applications were investigated: as adjuvants and as weight reduction agents.

Adjuvants are used in vaccines in order to enhance the immunological response towards attenuated and poorly immunogenic antigens. Their function can be mediated through dendritic cells which have a central role in the control of adaptive immunity including immunological memory. Our results show that different types of mesoporous silica particles were able to tune the development of T cells both in human cell cultures and in mice. In contrast to the approved adjuvant alum (aluminium salts) which is a specific inducer of Th2-type immune responses, the particles induced more Th1-like responses, which may be desired in vaccines against allergy and intracellular pathogens such as viruses. Particle exposure to macrophages did not affect their cell function which is crucial for tissue homeostasis, wound repair and in prevention of autoimmune responses. Likewise, the cytokine secretion was not affected, which suggest that macrophages would not modulate the immune response towards the particles.

Furthermore, mesoporous silica particles were highly tolerated at daily oral administrations of up to 2000 mg/kg doses for some of the materials prepared. Large pore mesoporous silica particles were shown to act as weight and body fat reduction agents without other observable pathological signs when administered in the diet of obese mice.

Together; those results are promising for the development of mesoporous silica as drug delivery systems and adjuvants for oral administration of drugs or vaccines. Additionally, large pore mesoporous silica materials are potential agents for the treatment of obesity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1023
Keyword [en]
mesoporous silica, biocompatibility, adjuvants, drug delivery systems, obesity
National Category
Nano Technology
Identifiers
URN: urn:nbn:se:uu:diva-195904ISBN: 978-91-554-8605-1 (print)OAI: oai:DiVA.org:uu-195904DiVA: diva2:608668
Public defence
2013-04-11, Polhemssalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 14:00 (English)
Opponent
Supervisors
Available from: 2013-03-21 Created: 2013-02-28 Last updated: 2013-05-02Bibliographically approved
List of papers
1. Efficient internalization of mesoporous silica particles of different sizes by primary human macrophages without impairment of macrophage clearance of apoptotic or antibody-opsonized target cells
Open this publication in new window or tab >>Efficient internalization of mesoporous silica particles of different sizes by primary human macrophages without impairment of macrophage clearance of apoptotic or antibody-opsonized target cells
Show others...
2009 (English)In: Toxicology and Applied Pharmacology, ISSN 0041-008X, E-ISSN 1096-0333, Vol. 239, no 3, 306-319 p.Article in journal (Refereed) Published
Abstract [en]

Macrophage recognition and ingestion of apoptotic cell corpses, a process referred to as programmed cell clearance, is of considerable importance for the maintenance of tissue homeostasis and in the resolution of inflammation. Moreover, macrophages are the first line of defense against microorganisms and other foreign materials including particles. However, there is sparse information on the mode of uptake of engineered nanomaterials by primary macrophages. In this study, mesoporous silica particles with cubic pore geometries and covalently fluorescein-grafted particles were synthesized through a novel route, and their interactions with primary human monocyte-derived macrophages were assessed. Efficient and active internalization of mesoporous silica particles of different sizes was observed by transmission electron microscopic and flow cytometric analysis and studies using pharmacological inhibitors suggested that uptake occurred through a process of endocytosis. Moreover, uptake of silica particles was independent of serum factors. The silica particles with very high surface areas due to their porous structure did not impair cell viability or function of macrophages, including the ingestion of different classes of apoptotic or opsonized target cells. The current findings are relevant to the development of mesoporous materials for drug delivery and other biomedical applications.

Keyword
Drug delivery, Endocytosis, Human monocyte-derived macrophages, Mesoporous silica particles, Programmed cell clearance
National Category
Engineering and Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-108064 (URN)10.1016/j.taap.2009.06.011 (DOI)000269677000011 ()19538981 (PubMedID)
Available from: 2009-09-04 Created: 2009-09-04 Last updated: 2017-12-13Bibliographically approved
2. Adjuvant Properties of Mesoporous Silica Particles Tune the Development of Effector T Cells
Open this publication in new window or tab >>Adjuvant Properties of Mesoporous Silica Particles Tune the Development of Effector T Cells
Show others...
2012 (English)In: Small, ISSN 1613-6810, Vol. 8, no 13, 2116-2124 p.Article in journal (Refereed) Published
Abstract [en]

Alum is the most frequently used adjuvant today, primarily inducing Th2 responses. However, Th1-type responses are often desirable within immune therapy, and therefore the development of new adjuvants is greatly needed. Mesoporous silica particles with a highly ordered pore structure have properties that make them very interesting for future controlled drug delivery systems, such as controllable particle and pore size; they also have the ability to induce minor immune modulatory effects, as previously demonstrated on human-monocyte-derived dendritic cells (MDDCs). In this study, mesoporous silica particles are shown to be efficiently engulfed by MDDCs within 2 h, probably by phagocytic uptake, as seen by confocal microscopy and transmission electron microscopy. A co-culture protocol is developed to evaluate the capability of MDDCs to stimulate the development of naive CD4+ T cells in different directions. The method, involving ELISpot as a readout system, demonstrates that MDDCs, after exposure to mesoporous silica particles (AMS-6 and SBA-15), are capable of tuning autologous naive T cells into different effector cells. Depending on the size and functionalization of the particles added to the cells, different cytokine patterns are detected. This suggests that mesoporous silica particles can be used as delivery vehicles with tunable adjuvant properties, which may be of importance for several medical applications, such as immune therapy and vaccination.

Place, publisher, year, edition, pages
John Wiley & Sons, 2012
Keyword
adjuvants, dendritic cells, immunology, mesoporous silica particles, naive T cells
National Category
Engineering and Technology Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-179024 (URN)10.1002/smll.201102620 (DOI)000306011500021 ()
Available from: 2012-08-06 Created: 2012-08-06 Last updated: 2016-11-30Bibliographically approved
3. Mesoporous silica particles potentiate antigen specific T cell responses
Open this publication in new window or tab >>Mesoporous silica particles potentiate antigen specific T cell responses
Show others...
2014 (English)In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 9, no 12, 1835-1846 p.Article in journal (Refereed) Published
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:uu:diva-195901 (URN)10.2217/nnm.13.170 (DOI)000343904800006 ()
Available from: 2013-02-28 Created: 2013-02-28 Last updated: 2017-12-06Bibliographically approved
4. In vivo oral toxicological evaluation of mesoporous silica particles
Open this publication in new window or tab >>In vivo oral toxicological evaluation of mesoporous silica particles
Show others...
2013 (English)In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 8, no 1, 57-64 p.Article in journal (Refereed) Published
Abstract [en]

Background: Mesoporous silica particles are highly promising nanomaterials for biomedical applications. They can be used to improve bioavailability, solubility and drug stability and to protect drugs from the acidic conditions of the stomach, leading to increased drug effectiveness. Their biocompatibility in vivo has recieved little attention, in particular regarding oral administration. Aim: To study the oral tolerance of micron-sized nanoporous folic acid-templated material-1 (cylindrical, 2D hexagonal pore structure) and nanometer-sized anionic-surfactant-templated mesoporous silica material-6 (cylindrical, 3D cubic pore structure) mesoporous silica particles in Sprague Dawley rats. Materials & methods: A dose stepwise procedure or range finding test was followed by a consequent confirmatory test. The confirmatory test included daily administrations of 2000 and 1200 mg/kg doses for nanoporous folic acid-templated material-1 and anionic-surfactant-templated mesoporous silica material-6, respectively. Results: The maximum tolerated dose for anionic-surfactant-templated mesoporous silica material-6 was not reached. Similar results were observed for nanometer-sized anionic-surfactant-templated mesoporous silica material-1 in most of the animals, although adverse effects were observed in some animals that are most probably due to the administration by oral gavage of the formulated particles. Conclusion: The results are promising for the use of mesoporous silica materials as drug-delivery systems in oral administration.

National Category
Natural Sciences Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-180100 (URN)10.2217/nnm.12.77 (DOI)000314577800014 ()22891863 (PubMedID)
Available from: 2012-08-29 Created: 2012-08-29 Last updated: 2017-12-07Bibliographically approved
5. Large pore mesoporous silica induced weight loss in obese mice
Open this publication in new window or tab >>Large pore mesoporous silica induced weight loss in obese mice
Show others...
2013 (English)In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 9, no 9, 1353-1362 p.Article in journal (Refereed) Published
Abstract [en]

Background: There is a need for medical treatments to curb the rising rate of obesity. Weight reduction is correlated with a decrease in associated risk factors and cholesterol levels in humans. Amorphous silica particles have been found to exert a hypocholesterolemic effect in humans, making them popular dietary additives. Aim: To investigate the effect of mesoporous silica, which possess sharp pore size distributions, on: weight loss, cholesterol, triglycerides and glucose blood levels in obese mice. Materials & methods: Mesoporous silicas with differing pore size were mixed in the high-fat diet of obese mice. Results: Animals receiving large pore mesoporous silica with a high-fat diet show a significant reduction in body weight and fat composition, with no observable negative effects. Conclusion: Pore size is an important parameter for reduction of body weight and body fat composition by mesoporous silica, demonstrating promising signs for the treatment of obesity.

Keyword
body fat, body weight, cholesterol, high-fat diet, mesoporous silica, obesity
National Category
Other Medical Biotechnology Engineering and Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-195903 (URN)10.2217/nnm.13.138 (DOI)000342071700012 ()24471500 (PubMedID)
Funder
Swedish Research Council, 2009-4716Novo NordiskSwedish Diabetes AssociationMagnus Bergvall FoundationCarl Tryggers foundation
Available from: 2013-02-28 Created: 2013-02-28 Last updated: 2017-07-05Bibliographically approved

Open Access in DiVA

fulltext(3596 kB)1402 downloads
File information
File name FULLTEXT01.pdfFile size 3596 kBChecksum SHA-512
27980ac14b3201372971dfba9bdf3680266b18715239f525478f4208390cf164c063b31a9e870cc326ebc4f6b11e53cb7c50184f3855b4fff89ac3c4258619da
Type fulltextMimetype application/pdf
Buy this publication >>

Search in DiVA

By author/editor
Kupferschmidt, Natalia
By organisation
Nanotechnology and Functional Materials
Nano Technology

Search outside of DiVA

GoogleGoogle Scholar
Total: 1402 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 823 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • 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