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Environment-Sensitive Multifunctional Drug Delivery Systems
KTH, School of Information and Communication Technology (ICT), Material Physics, Functional Materials, FNM.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Drug delivery systems (DDS) with multiple functionalities such as environment-sensitive drug release mechanisms and visualization agents have motivated the biomedical community as well as materials chemists for more than a decade. This dissertation is concerned with the development of nanoparticles for multifunctional DDS  to tackle several crucial challenges in these complex systems, including polymeric nanospheres which respond to temperature change, superparamagnetic iron oxide nanoparticles/polymeric composite for magnetic resonance imaging contrast agents and drug carriers, immunoresponse of nanomaterials and injectable magnetic field sensitive ferrogels.

The biocompatible and biodegradable polylactide (PLA) was employed as matrix materials for polymeric nanosphere-based DDS. The thermosensitive polymeric nanospheres have been constructed through a “modified double-emulsion method”. The inner shell containing the thermosensitive poly(N-isopropylacrylamide) (PNIPAAm) undergoes a “hydrophilic-to-hydrophobic” phase transition around the human body temperature. The sensitivity of the polymer to the temperature can facilitate drug release at an elevated temperature upon administration. In addition, gold nanoparticles were assembled on the dual-shell structure to form a layer of gold shell. The cell viability was found to be enhanced due to the gold layer. The immunoresponse of the gold nanoparticles has been considered even if no acute cytotoxicity was observed.

Imaging is another functionality of multifunctional DDS. This work focuses on magnetic resonance imaging (MRI) and involves synthesis and surface modification of superparamagnetic iron oxide nanoparticles (SPIONs) for contrast agents. The SPIONs have been prepared through a high temperature decomposition method. Surface modification was carried out in different ways. Poly(L,L-lactide) (PLLA) was grafted on SPIONs through surface-initiated ring-opening polymerization. The hydrophobic model drug indomethacin was loaded in the PLLA layer of the composite particles. For biomedical applications, it is essential to modify the hydrophobic particles so that they can be dispersed in physiological solutions. A series of protocols including using small charged molecules and amphiphilic polymers has been established. Pluronic F127 (PF127), a triblock copolymer was applied as a phase transfer reagent. Most interestingly, PF127@SPIONs show remarkable efficacy as T2 contrast agents. The PF127@SPIONs have been successfully applied to image the cochlea in a rat model. As another phase transfer reagent, poly(maleic anhydride-alt-octadecene)-graft-PNIPAAm (PMAO-graft-PNIPAAm) was created for surface modification of SPIONs. This new copolymer provides the modified SPIONs with thermosensitivity together with water-dispersibility.

As another form of DDS, ferrogel made of PF127 copolymer and SPIONs was developed. Gelation process depends on the temperature of the SPIONs/PF127 mixture. This property makes it possible to use the ferrogel as an injectable drug carrier. Unlike other ferrogels based on crosslinked polymeric network, the PF127 ferrogel can entrap and release hydrophobic drugs. Application of an external magnetic field is found to enhance the drug release rate. This property can find application in externally stimulated local drug release applications.

Place, publisher, year, edition, pages
Stockholm: KTH , 2010. , 86 p.
Series
Trita-ICT/MAP AVH, ISSN 1653-7610 ; 1
National Category
Materials Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-12053ISBN: 978-91-7415-576-1 (print)OAI: oai:DiVA.org:kth-12053DiVA: diva2:300480
Public defence
2010-03-19, C2, Electrum, Isafjordsgatan 26, Kista, 10:00 (English)
Opponent
Supervisors
Note
QC20100722Available from: 2010-03-02 Created: 2010-02-26 Last updated: 2010-07-22Bibliographically approved
List of papers
1. Thermosensitive nanospheres with a gold layer revealed as low-cytotoxic drug vehicles
Open this publication in new window or tab >>Thermosensitive nanospheres with a gold layer revealed as low-cytotoxic drug vehicles
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2005 (English)In: Langmuir, ISSN 0743-7463, E-ISSN 1520-5827, Vol. 21, no 20, 9346-9351 p.Article in journal (Refereed) Published
Abstract [en]

In this paper, the positive effect of a gold layer on cell viability is demonstrated by examining the results given by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfop henyl)-2H-tetrazolium (MTS) assay and two-color cell fluorescence viability (TCCV) assay. These cytotoxicity tests were performed with human cervical adenocarcinoma cells (HeLa cell line) and transformed African green monkey kidney fibroblast cells (Cos-7 cell line). To fabricate the nanostructures as drug vehicles, first, poly((L),(L)-lactidec-co-ethylene glycol) (PLLA-PEG) and poly(N-isopropylacrylamide-co-(D),(D)-lactide) (PNIPAAm-PDLA) were synthesized, and then two kinds of thermosensitive nanospheres comprising "shell-in-shell" structures without a gold layer (PLLA-PEG@PNIPAAm-PDLA) and with a gold layer (Au@PLLA-PEG@PNIPAAmPDLA) were constructed by a modified double-emulsion method (MDEM). Both of them displayed a unique thermosensitive character exhibiting the lower critical solubility temperature (LCST) at 36.7 degrees C which was confirmed by LTV-vis spectroscopy and differential scanning calorimetry (DSC). The release profiles of entrapped bovine serum albumin (BSA) were monitored at 22 and 37 degrees C, respectively, to reveal the thermal dependence on the release rate. In cell viability tests, both PLLA-PEG@PNIPAAm-PDLA and Au@PLLAPEGCd)PNIPAAm-PDLA showed excellent cell viability, and furthermore, Au@PLLA-PEG@PNIPAAmPDLA, particularly at high doses, exhibited more enhanced cell viability than PLLA-PEGCa)PNTPAAm-PDLA. This effect is mainly attributed to the gold layer which binds the protein molecules first and consequently facilitates transmembrane uptake of essential nutrients in the cell media, resulting in favorable cell proliferation.

Keyword
colorimetric detection, bicinchoninic acid, silver-enhancement, polymeric micelles, block-copolymers, nanoparticles, delivery, surface, poly(n-isopropylacrylamide), cells
National Category
Materials Chemistry
Identifiers
urn:nbn:se:kth:diva-12080 (URN)10.1021/la051069t (DOI)000232080100054 ()2-s2.0-26444590043 (Scopus ID)
Note
QC 20100720Available from: 2010-03-03 Created: 2010-03-02 Last updated: 2017-12-12Bibliographically approved
2. The importance of an endotoxin-free environment during the production of nanoparticles used in medical applications
Open this publication in new window or tab >>The importance of an endotoxin-free environment during the production of nanoparticles used in medical applications
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2006 (English)In: Nano letters (Print), ISSN 1530-6984, E-ISSN 1530-6992, Vol. 6, no 8, 1682-1686 p.Article in journal (Refereed) Published
Abstract [en]

We investigated the effect of spherical gold nanoparticles on immature dendritic cells (DCs). Conventionally produced nanoparticles had a maturating effect on the DCs-a result of lipopolysaccharide (LPS) contamination. By modification of the production process, low-LPS particles were obtained, which had practically no effect on phenotypic maturation or cytokine production of the DCs. Our findings emphasize the importance of high purity in the production of nanoparticles, since possible contaminants may interfere with the assessment of biological/medical effects. They also highlight that nanoparticles can function as carriers of immune modulating contaminants.

Keyword
human dendritic cells, gold, immunity, lipopolysaccharide, contamination, maturation, particles, receptor, innate, metal
National Category
Materials Chemistry
Identifiers
urn:nbn:se:kth:diva-12100 (URN)10.1021/nl060860z (DOI)000239623900019 ()2-s2.0-33748329694 (Scopus ID)
Note
QC 20100721Available from: 2010-03-03 Created: 2010-03-03 Last updated: 2017-12-12Bibliographically approved
3. A high-performance magnetic resonance imaging T2 contrast agent
Open this publication in new window or tab >>A high-performance magnetic resonance imaging T2 contrast agent
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2007 (English)In: Advanced Materials, ISSN 0935-9648, E-ISSN 1521-4095, Vol. 19, no 14, 1874-1878 p.Article in journal (Refereed) Published
Abstract [en]

A high-performance magnetic resonance imaging T-2 contrast agent has been prepared via phase transfer of hydrophobic superparamagnetic iron oxide nanoparticles (SPIONs) to an aqueous solution by using Pluronic F127 copolymers. As seen in the figure, a hierarchical structure of the surface coating is formed and proven to be a crucial characteristic to enhance not only water dispersibility, but also the efficacy as a T-2 contrast agent.

Keyword
superparamagnetic iron-oxide, aqueous-solutions, block-copolymers, nanocrystals, nanoparticles, water, mri, size, micelles, media
National Category
Engineering and Technology
Identifiers
urn:nbn:se:kth:diva-7079 (URN)10.1002/adma.200602326 (DOI)000248323800018 ()2-s2.0-34547480782 (Scopus ID)
Note
QC 20100721Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2017-12-14Bibliographically approved
4. Cubic versus spherical magnetic nanoparticles: The role of surface anisotropy
Open this publication in new window or tab >>Cubic versus spherical magnetic nanoparticles: The role of surface anisotropy
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2008 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 130, no 40, 13234-13239 p.Article in journal (Refereed) Published
Abstract [en]

The magnetic properties of maghemite (gamma-Fe2O3) cubic and spherical nanoparticles of similar sizes have been experimentally and theoretically studied. The blocking temperature, TB, of the nanoparticles depends on their shape, with the spherical ones exhibiting larger TB. Other low temperature properties such as saturation magnetization, coercivity, loop shift or spin canting are rather similar. The experimental effective anisotropy and the Monte Carlo simulations indicate that the different random surface anisotropy of the two morphologies combined with the low magnetocrystalline anisotropy of gamma-Fe2O3 is the origin of these effects.

Keyword
GAMMA-FE2O3 NANOPARTICLES, OXIDE NANOPARTICLES, FINE PARTICLES, NANOCRYSTALS, MAGHEMITE, FERRITE, COBALT, BEHAVIOR, MOMENT, SHAPE
Identifiers
urn:nbn:se:kth:diva-12103 (URN)10.1021/ja0768744 (DOI)000259675500022 ()2-s2.0-53549110552 (Scopus ID)
Note
QC20100721Available from: 2010-03-04 Created: 2010-03-04 Last updated: 2017-12-12Bibliographically approved
5. 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
6. Coating Nanocrystals with Amphiphilic Thermosensitive Copolymers
Open this publication in new window or tab >>Coating Nanocrystals with Amphiphilic Thermosensitive Copolymers
2009 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 48, no 42, 7845-7849 p.Article in journal (Refereed) Published
Abstract [en]

Well-dressed: A new method was developed to produce thermosensitive nanocrystals (NCs) by coating the NCs with an amphiphilic copolymer consisting of poly(maleic anhydride-alt-1-octadecene) (PMAO) and poly(N-isopropylacrylamide) (PNIPAAm; see photograph of coated Fe3O4 NCs at 20 °C and 40 °C). The method is general for all hydrophobic NCs produced by thermolysis.

Keyword
block copolymers, lipophilicity, magnetic properties, nanostructures, GOLD NANOPARTICLES, HYDROPHOBIC NANOCRYSTALS, MAGNETIC NANOPARTICLES, POLYMER, TEMPERATURE, MICROGELS, SHELL
Identifiers
urn:nbn:se:kth:diva-12105 (URN)10.1002/anie.200900489 (DOI)000270846600021 ()2-s2.0-70349705486 (Scopus ID)
Note
QC20100722Available 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. Visualization and Analysis of Superparamagnetic Ferrogels in the Inner Ear by Light Microscopy and Energy Filtred TEM: a promising approach for advanced local drug delivery
Open this publication in new window or tab >>Visualization and Analysis of Superparamagnetic Ferrogels in the Inner Ear by Light Microscopy and Energy Filtred TEM: a promising approach for advanced local drug delivery
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(English)In: Journal of Microscopy, ISSN 0022-2720, E-ISSN 1365-2818Article in journal (Other academic) Submitted
Identifiers
urn:nbn:se:kth:diva-14165 (URN)
Note
QC20100722Available from: 2010-07-22 Created: 2010-07-22 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

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