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Multifunctional nanomaterials for diagnostic and therapeutic applications
KTH, School of Information and Communication Technology (ICT), Material Physics, Functional Materials, FNM.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the past few years, the use of nanostructured materials in medical applications hasdramatically increased, both in the research phase and for clinical purposes, due to thepeculiar properties and the ability of such materials to interact at a similar scale withbiological entities. In this thesis, we developed tailored magnetic multifunctionalnanoparticles for diagnostic and therapeutic applications, such as detection ofbiomolecules, simultaneous enhanced magnetic resonance imaging (MRI), fluorescentvisualization and controlled drug release.For sensitive and selective detection of specific biomolecules, thermally blocked ironoxide nanoparticles with tailored magnetic properties were developed. The formation ofsuch nanoparticles has been studied both in terms of size and magnetic behavior in liquidsuspension or in polymer matrixes. These particles with narrow size distribution (averagediameter of 19 nm) were surface functionalized by antigen molecules and were used forthe detection of Brucella antibodies in biological samples. The binding of biomoleculesresults in an increase in the particle’s hydrodynamic diameter, affecting the relaxationbehavior that was monitored by magnetic measurements. This sensing system is a fastand sensitive biosensor with very low detection limits (0.05 μg/mL).Superparamagnetic iron oxide nanoparticles (SPION) have been synthesized withaverage diameter of 10-12 nm, narrow size distribution, high crystallinity and superiormagnetic properties as liquid suspensions or embedded in a bulk transparent magneticnanocomposite. These nanoparticles were synthesized in organic solvents and, after phasetransfer with Pluronic F127 amphiphilic copolymer, show excellent relaxivity properties(high r2/r1 ratio) and great contrast enhancement in T2 weighted MRI, confirmed by invivostudies of rat inner ear.SPION have been used as a component for different multifunctional nanostructures. Thefirst system based on poly (L,L lactide)-methoxy polyethylene glycol (PLLA-mPEG)copolymer has been prepared by an emulsion/evaporation process that lead to polymericnanoparticles containing several imaging agents, such as SPION, quantum dots (QDs)and gold nanorods as well as indomethacin (IMC) as therapeutic payload. With a similarprocedure, but using poly (lactide-co-glycolide) (PLGA-PEG-NH2) copolymer, a secondtype of multifunctional nanoparticles has been obtained. Their size can be tailored from70 to 150 nm varying synthesis parameters, such as the surfactant concentration or waterto oil ratio. Both these polymer-based multifunctional nanoparticles can be visualized byfluorescence microscopy (QDs photoemission) and MRI (SPION magnetization) and theycan be used for photothermal therapy (gold nanorods) and drug delivery. The last systemconsists of SPION nanoparticles coated with PLLA directly on the surface by an in-situpolymerization process. A hydrophobic drug was loaded before the phase transfer withPluronic F127 and these nanoparticles show simultaneous MRI T2 contrast enhancementas well as high drug loading and sustained delivery.Controlling the drug release rate is also a critical parameter for tailored therapeutictreatments, and for this reason we developed a novel drug delivery system based on theintegration of SPION and Pluronic F127 gels. IMC was loaded in the ferrogel (with atailored gelation temperature) and its release rate was triggered by applying an externalmagnetic field owing to the SPION magnetic properties.

Place, publisher, year, edition, pages
Stockholm: KTH , 2010. , xii, 70 p.
Series
Trita-ICT/MAP AVH, ISSN 1653-7610 ; 2010:11
National Category
Dentistry
Identifiers
URN: urn:nbn:se:kth:diva-26788ISBN: 978-91-7415-803-8 (print)OAI: oai:DiVA.org:kth-26788DiVA: diva2:372726
Public defence
2010-12-17, C2, KTH-Electrum, Isafjordsgatan 24, Kista, 13:30 (English)
Opponent
Supervisors
Note
QC 20101207Available from: 2010-12-07 Created: 2010-11-26 Last updated: 2010-12-07Bibliographically approved
List of papers
1. Tailored Magnetic Nanoparticles for Direct and Sensitive Detection of Biomolecules in Biological Samples
Open this publication in new window or tab >>Tailored Magnetic Nanoparticles for Direct and Sensitive Detection of Biomolecules in Biological Samples
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2008 (English)In: Nano letters (Print), ISSN 1530-6984, E-ISSN 1530-6992, Vol. 8, no 10, 3423-3428 p.Article in journal (Refereed) Published
Abstract [en]

We developed nanoparticles with tailored magnetic properties for sensitive detection of biomolecules directly in biological samples in a single step. Thermally blocked nanoparticles obtained by thermal hydrolysis are mixed with sample solutions and the variation of the magnetic relaxation due to surface binding is used to detect the presence of biomolecules. The binding events significantly increase the hydrodynamic volume of nanoparticles, thus changing their Brownian relaxation frequency which is measured by a specifically developed AC-susceptometer.

The system was tested for the presence of Brucella antibodies in serum samples from infected cows and the surface of the nanoparticles was functionalized with lipopolysaccarides (LPS) from Brucella abortus. The hydrodynamic volume of functionalized particles increased by 25-35% as a result of the binding of the antibodies, as measured by changes in the susceptibility in an alternating magnetic field. The method has shown high sensitivity, with detection limit of 7 nmol·L-1 in serum without any pre-treatment of the biological samples.

The detection method is very sensitive, cost-efficient and versatile, giving a direct indication if the animal is infected or not, making it suitable for point-of care applications. The functionalization of tailored magnetic nanoparticles can be modified to suit numerous homogenous assays for a wide range of applications.

Keyword
BRUCELLA-ABORTUS, RELAXATION, ANTIBODIES, PARTICLES
National Category
Natural Sciences
Identifiers
urn:nbn:se:kth:diva-9231 (URN)10.1021/nl8022498 (DOI)000259906800064 ()2-s2.0-56149116406 (Scopus ID)
Note

QC 20101001

Available from: 2008-10-10 Created: 2008-10-10 Last updated: 2017-12-11Bibliographically approved
2. Polymeric/inorganic multifunctional nanoparticles for simultaneous drug delivery and visualization
Open this publication in new window or tab >>Polymeric/inorganic multifunctional nanoparticles for simultaneous drug delivery and visualization
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2010 (English)In: Materials Research Society Symposium Proceedings, ISSN 0272-9172, E-ISSN 1946-4274, Vol. 1257Article in journal (Refereed) Published
Abstract [en]

Nanoparticles consisting of different biocompatible materials are attracting a lot of interest in the biomedical area as useful tools for drug delivery, photo-therapy and contrast enhancement agents in MRI, fluorescence and confocal microscopy. This work mainly focuses on the synthesis of polymeric/inorganic multifunctional nanoparticles (PIMN) based on biocompatible di-block copolymer poly(L,L-lactide-co-ethylene glycol) (PLLA-PEG) via an emulsion-evaporation method. Besides containing a hydrophobic drug (Indomethacin), these polymeric nanoparticles incorporate different visualization agents such as superparamagnetic iron oxide nanoparticles (SPION) and fluorescent Quantum Dots (QDs) that are used as contrast agents for Magnetic Resonance Imaging (MRI) and fluorescence microscopy together. Gold Nanorods are also incorporated in such nanostructures to allow simultaneous visualization and photodynamic therapy. MRI studies are performed with different loading of SPION into PIMN, showing an enhancement in T2 contrast superior to commercial contrast agents. Core-shell QDs absorption and emission spectra are recorded before and after their loading into PIMN. With these polymeric/inorganic multifunctional nanoparticles, both MRI visualization and confocal fluorescence microscopy studies can be performed. Gold nanorods are also synthesized and incorporated into PIMN without changing their longitudinal absorption peak usable for lased excitation and phototherapy. In-vitro cytotoxicity studies have also been performed to confirm the low cytotoxicity of PIMN for further in-vivo studies.

National Category
Materials Engineering
Identifiers
urn:nbn:se:kth:diva-26782 (URN)10.1557/PROC-1257-O04-03 (DOI)2-s2.0-79951616373 (Scopus ID)
Note
QC 20101202Available from: 2010-11-26 Created: 2010-11-26 Last updated: 2017-12-12Bibliographically approved
3. Evolution of Structural and Magnetic Properties of Magnetite Nanoparticles for Biomedical Applications
Open this publication in new window or tab >>Evolution of Structural and Magnetic Properties of Magnetite Nanoparticles for Biomedical Applications
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2010 (English)In: Crystal Growth & Design, ISSN 1528-7483, E-ISSN 1528-7505, Vol. 10, no 5, 2278-2284 p.Article in journal (Refereed) Published
Abstract [en]

We have investigated the evolution of microstructure and magnetic properties of thermally blocked magnetite nanoparticles, aimed for immunoassay applications, during their synthesis. High-resolution transmission electron microscopy (HRTEM) investigations of the size, size distribution, morphology, and crystal structure of particles reveal that particles at an early stage of the reaction process are either single crystals or polycrystals containing planar faults and they grow via a combination of reactant (monomer) consumption and oriented attachment at specific crystallographic surfaces because of the strong dipolar character of the < 111 > surfaces of magnetite. At a later stage of the synthesis reaction, the magnetic attraction strives to align contacting particles with their < 111 > axis of easy magnetization in parallel and this may also be an active driving force for crystal growth. At latter stages, the crystal growth is dominated by Ostwald ripening leading to smoother crystalline particles with a mean diameter of 16.7 +/- 3.5 nm and a narrow size distribution. The magnetic properties of the particles measured using static and dynamic magnetic fields are consistent with the evolution of particle size and structure and show the transition from superparamagnetic to thermally blocked behavior needed for magnetic relaxation-based immunoassay applications.

Keyword
IMPERFECT ORIENTED ATTACHMENT, MAGNETOTACTIC BACTERIA, NANOCRYSTALLINE ZNS, DEFECT GENERATION, GROWTH-KINETICS, CRYSTAL-GROWTH, PARTICLES, ORGANIZATION, ACCRETION, DYNAMICS
National Category
Materials Chemistry
Identifiers
urn:nbn:se:kth:diva-9567 (URN)10.1021/cg901602w (DOI)000277273900040 ()2-s2.0-77952053462 (Scopus ID)
Note
QC 20101110 Uppdaterad från manuskript till artikel (20101110).Available from: 2008-11-14 Created: 2008-11-14 Last updated: 2017-12-14Bibliographically approved
4. PLGA-PEG multifunctional nanoparticles for simultaneous drug delivery and visualization
Open this publication in new window or tab >>PLGA-PEG multifunctional nanoparticles for simultaneous drug delivery and visualization
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(English)In: Journal of nanoparticle research, ISSN 1388-0764, E-ISSN 1572-896XArticle in journal (Other academic) Submitted
National Category
Dentistry
Identifiers
urn:nbn:se:kth:diva-26783 (URN)
Note
QS 20120326Available from: 2010-11-26 Created: 2010-11-26 Last updated: 2017-12-12Bibliographically approved
5. Bifunctional polylactide coated iron oxide nanoparticles for drug delivery and MRI contrast enhancement
Open this publication in new window or tab >>Bifunctional polylactide coated iron oxide nanoparticles for drug delivery and MRI contrast enhancement
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(English)In: Advanced Materials, ISSN 0935-9648, E-ISSN 1521-4095Article in journal (Other academic) Submitted
National Category
Medical Laboratory and Measurements Technologies
Identifiers
urn:nbn:se:kth:diva-26784 (URN)
Note
QS 20120326Available from: 2010-11-26 Created: 2010-11-26 Last updated: 2017-12-12Bibliographically approved
6. Injectable Superparamagnetic Ferrogels for Controlled Release of Hydrophobic Drugs
Open this publication in new window or tab >>Injectable Superparamagnetic Ferrogels for Controlled Release of Hydrophobic Drugs
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2009 (English)In: Advanced Materials, ISSN 0935-9648, E-ISSN 1521-4095, Vol. 21, no 13, 1354-1357 p.Article in journal (Refereed) Published
Abstract [en]

A ferrogel for magnetically controlled release of drugs is prepared by integration of superparamagnetic iron oxide nanoparticles and Pluronic F127 gels. The hydrophobic drug indomethacin is loaded in the ferrogel owing to the oil-in-water micellar structure. The characteristic solgel transition property renders the ferrogel an injectable drug carrier that will be, in principle, free from surgical implant procedure.

Keyword
BLOCK-COPOLYMER SOLUTIONS, PLURONIC F-127 GELS, MAGNETIC NANOPARTICLES, AQUEOUS-SOLUTION, IN-VITRO, BEHAVIOR, DELIVERY, HYDROGELS, SOLUBILIZATION, NANOCRYSTALS
National Category
Materials Chemistry
Identifiers
urn:nbn:se:kth:diva-12104 (URN)10.1002/adma.200800764 (DOI)000265432700008 ()2-s2.0-66149153430 (Scopus ID)
Note
QC 20100722Available from: 2010-03-04 Created: 2010-03-04 Last updated: 2017-12-12Bibliographically approved
7. MRI of the Cochlea with Superparamagnetic Iron Oxide Nanoparticles Compared to Gadolinium Chelate Contrast Agents in a Rat Mode
Open this publication in new window or tab >>MRI of the Cochlea with Superparamagnetic Iron Oxide Nanoparticles Compared to Gadolinium Chelate Contrast Agents in a Rat Mode
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2009 (English)In: European Journal of Nanomedicine, ISSN 1662-5986, Vol. 2, no 2, 29-36 p.Article in journal (Refereed) Published
Keyword
animal, contrast agent, linner ear, fluids, MRI, nanotechnology, neuron
National Category
Engineering and Technology
Identifiers
urn:nbn:se:kth:diva-12106 (URN)2-s2.0-79551699165 (Scopus ID)
Note

QC 20101210

Available from: 2010-03-04 Created: 2010-03-04 Last updated: 2017-04-28Bibliographically approved
8. Synthesis and magnetic properties of bulk transparent PMMA/Fe-oxide nanocomposites
Open this publication in new window or tab >>Synthesis and magnetic properties of bulk transparent PMMA/Fe-oxide nanocomposites
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2009 (English)In: Nanotechnology, ISSN 0957-4484, E-ISSN 1361-6528, Vol. 20, no 18Article in journal (Refereed) Published
Abstract [en]

PMMA/Fe-oxide nanocomposites are fabricated by a chemical method. Monodispersed Fe-oxide nanoparticles are well dispersed in the PMMA matrix by in situ polymerization, resulting in a bulk transparent polymeric nanocomposite. The magnetic behavior of the PMMA/Fe-oxide nanocomposites is investigated. The transparent PMMA/Fe-oxide nanocomposite has potentially interesting magneto-optic applications without compromising the advantages of a lightweight, noncorrosive polymeric material with very high transparency even for bulk samples.

Keyword
sol-gel process, iron nanoparticles, particles, polymerization, intercalation, composites, silicates, mechanism, films
Identifiers
urn:nbn:se:kth:diva-18351 (URN)10.1088/0957-4484/20/18/185607 (DOI)000265252900022 ()2-s2.0-65549141767 (Scopus ID)
Note
QC 20100525Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2017-12-12Bibliographically approved
9. MRI manifestation of novel superparamagnetic iron oxide nanoparticles in the rat inner ear
Open this publication in new window or tab >>MRI manifestation of novel superparamagnetic iron oxide nanoparticles in the rat inner ear
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2010 (English)In: Nanomedicine, ISSN 1743-5889, Vol. 5, no 5, 739-754 p.Article in journal (Refereed) Published
Abstract [en]

Aim: Superparamagnetic iron oxide nanoparticles hierarchically coated with oleic acid and Pluronic F127 copolymers (POA@SPION) have shown exceptional 12 contrast enhancement. The aim of the present work was to investigate the MRI manifestation of POA@SPION in the inner ear. Materials & methods: A total of 26 male Wister rats were selected for testing POA@SPION administered through intracochlear, intratympanic and intravenous routes. MRI was performed with a 4.7 T MR scanner. Results & conclusion: POA@SPION can be introduced into the perilymph space, after which it becomes widely distributed and can demonstrate the integrity of the perilymph-endolymph barrier. Positive highlighting of the endolymph compartment against the darkened perilymph was visualized for the first time. POA@SPION passed through the middle-inner ear barriers in only small amounts, but stayed in the perilymph for 3 days. They did not traverse the blood-perilymph barrier or blood-endolymph barrier. The inner ear distribution of POA@SPION was confirmed by histology. POA@SPION is a promising T2 negative contrast agent.

Keyword
animal, biological barrier, biomaterial, contrast agent inner ear fluids, MRI, nanoparticle, superparamagnetic iron oxide nanoparticles, tight junction
National Category
Medical Laboratory and Measurements Technologies
Identifiers
urn:nbn:se:kth:diva-14166 (URN)10.2217/nnm.10.45 (DOI)000280454400015 ()20662645 (PubMedID)2-s2.0-77954918617 (Scopus ID)
Note
QC 20100722 Uppdaterad från submitted till published (20110211).Available from: 2010-07-22 Created: 2010-07-22 Last updated: 2011-02-11Bibliographically approved
10. Visualization and Analysis of Superparamagnetic Iron Oxide Nanoparticles in the Inner Ear by Light Microscopy and Energy Filtered TEM
Open this publication in new window or tab >>Visualization and Analysis of Superparamagnetic Iron Oxide Nanoparticles in the Inner Ear by Light Microscopy and Energy Filtered TEM
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2011 (English)In: Nanomedicine: Nanotechnology, Biology, and Medicine, ISSN 1549-9634, Vol. 7, no 3, 360-369 p.Article in journal (Refereed) Published
Abstract [en]

Nanoparticles as potential carriers for local drug transfer are an alternative to systemic drug delivery into the inner ear. We report on the first in vitro tests of a new ferrogel consisting of superparamagnetic iron oxide nanoparticles (SPIONs) and a Pluronic (R) F127 (PF127) copolymer. Pluronic copolymers possess a unique viscosity-adjustable property that makes PF127 gels easy to handle compared to conventional cross-linked hydrogels. This ferrogel was successfully tested in cadaver human temporal bones as well as in organotypic explant cultures of mouse inner ears. SPIONs were identified by light microscopy and localized with different imaging modes in energy-filtered transmission electron microscopy. Our approach shows a promising possibility to use iron oxide nanoparticles, which are suitable for visualization and characterization at both the light- and electron-microscopic levels.

From the Clinical Editor: The authors report the first in vitro tests of a new ferrogel consisting of superparamagnetic iron oxide nanoparticles (SPIONs) and a Pluronic (R) F127 (PF127) copolymer for drug delivery in the inner ear, demonstrasting a promising possibility to use iron oxide nanoparticles, which are suitable for visualization and characterization at both the light- and electron-microscopic levels.

Keyword
Energy filtered transmission electron microscopy, Organotypic inner ear explant culture, Human temporal bone, Iron oxide nanoparticles
National Category
Engineering and Technology
Identifiers
urn:nbn:se:kth:diva-26787 (URN)10.1016/j.nano.2010.11.005 (DOI)000291032800013 ()2-s2.0-79956340120 (Scopus ID)
Note
QC 20101210 Uppdaterad från submitted till published (20110627).Available from: 2010-11-26 Created: 2010-11-26 Last updated: 2011-06-27Bibliographically approved
11. Synthesis, characterization and magneto-optical properties of transparent magnetic PMMA/nanoparticles composite
Open this publication in new window or tab >>Synthesis, characterization and magneto-optical properties of transparent magnetic PMMA/nanoparticles composite
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Engineering and Technology
Identifiers
urn:nbn:se:kth:diva-26785 (URN)
Note
QC 20101208Available from: 2010-11-26 Created: 2010-11-26 Last updated: 2010-12-08Bibliographically approved

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