Development of nanoscale delivery systems for breast cancer treatment
Author: Zhang, Yuning
Date: 2015-05-29
Location: Farmakologens föreläsningssal, Nanna Svartz väg 2, Karolinska Institutet, Solna
Time: 09.00
Department: Institutet för miljömedicin / Institute of Environmental Medicine
View/ Open:
Thesis_Yuning_Zhang.pdf (2.281Mb)
Abstract
Nanoparticle (NP) assisted diagnosis and drug delivery for antitumor applications have been widely investigated in the past few decades. To date, some of them have been approved for clinical applications and many more of them are under clinical trials. Although some progress has been achieved, it is still necessary to explore novel materials for antitumor applications. The work summarized in this thesis focused on organic NPs, and evaluated engineered polymer NPs and protein-lipid NPs as antitumor drug delivery systems in vitro. And a multifunctional fluorinated NP system was also assessed as theranostic (the combination of therapy and diagnosis) platform.
In paper I, two types of 2,2 bis(hydroxymethyl) propionic acid (bis-MPA) based dendritic- linear (DL) polymers were synthesized. One type has the hyperbranched (HB) dendritic structure while the other has dendrons (perfectly branched structures). HBDL and DL materials were compared as drug delivery systems in respect to their synthesis difficulty, quality of micelle formation and efficiency in drug delivery. It was found that HBDL can be synthesized in large scales and drug loaded HBDL tended to have stronger efficacy compared to DL, therefore it is a promising alterative to DL in anticancer drug delivery.
Further, in paper II, a detailed study regarding the uptake profile of a bis-MPA based hyperbranched copolymer micelle was conducted. The NP consisted of a Boltorn-H30 core (hyperbranched polyester) and PEG10k hydrophilic tails. It was found that the hyperbranched NP can be internalized into breast cancer cells via clathrin-dependent and macropinocytosis-mediated pathway through a time, concentration and energy dependent process.
In paper III, fluorinated copolymers micelles were synthesized and evaluated as theranostic system, which has both diagnostic and therapeutic functions. The consequent micelles were able to load and release doxorubicin (DOX) and demonstrated similar efficacy compared to free (non- formulated) DOX. Also these NPs could generate a detectable signal for 19F-MRI in vitro.
In paper IV, unimolecular NPs were developed from polyester based hyperbranched dendritic- linear polymers (HBDLPs). Such micelles were homogenous and did not have critical micelle concentration (CMC). And they were able to load DOX and delivery the drug into breast cancer cells. One HBDLP based NP containing a fluorinated polymer fragment was also synthesized to prove that these unimolecular systems are potentially useful as theranostic platforms.
In paper V, histamine functionalized copolymer micelles were developed in order to introduce pH responsive property to NPs and achieve endo-lysosomal escape. These NPs were non-toxic and capable of loading and release DOX. Drug loaded NPs exhibited significant enhanced inhibition of mitochondria function in breast cancer cells during short periods (12 h) compared to free DOX. Although the expected pH responsive behaviour was not observed for the in vitro drug release model, NPs with histamine functionalization demonstrated partly endo-lysosomal escape property, in particular for those with 50% histamine modification. Intracellular tracking of NPs revealed that they could escape from endo-lysosomes and relocate DOX into mitochondria and the nuclei.
In paper VI, lipoprotein like NP systems were developed by incorporating Saposin A, phospholipids and selected hydrophobic cargos. Such systems were shown to have promise as drug delivery platforms and to serve as NP based vaccine stabilizers.
In paper I, two types of 2,2 bis(hydroxymethyl) propionic acid (bis-MPA) based dendritic- linear (DL) polymers were synthesized. One type has the hyperbranched (HB) dendritic structure while the other has dendrons (perfectly branched structures). HBDL and DL materials were compared as drug delivery systems in respect to their synthesis difficulty, quality of micelle formation and efficiency in drug delivery. It was found that HBDL can be synthesized in large scales and drug loaded HBDL tended to have stronger efficacy compared to DL, therefore it is a promising alterative to DL in anticancer drug delivery.
Further, in paper II, a detailed study regarding the uptake profile of a bis-MPA based hyperbranched copolymer micelle was conducted. The NP consisted of a Boltorn-H30 core (hyperbranched polyester) and PEG10k hydrophilic tails. It was found that the hyperbranched NP can be internalized into breast cancer cells via clathrin-dependent and macropinocytosis-mediated pathway through a time, concentration and energy dependent process.
In paper III, fluorinated copolymers micelles were synthesized and evaluated as theranostic system, which has both diagnostic and therapeutic functions. The consequent micelles were able to load and release doxorubicin (DOX) and demonstrated similar efficacy compared to free (non- formulated) DOX. Also these NPs could generate a detectable signal for 19F-MRI in vitro.
In paper IV, unimolecular NPs were developed from polyester based hyperbranched dendritic- linear polymers (HBDLPs). Such micelles were homogenous and did not have critical micelle concentration (CMC). And they were able to load DOX and delivery the drug into breast cancer cells. One HBDLP based NP containing a fluorinated polymer fragment was also synthesized to prove that these unimolecular systems are potentially useful as theranostic platforms.
In paper V, histamine functionalized copolymer micelles were developed in order to introduce pH responsive property to NPs and achieve endo-lysosomal escape. These NPs were non-toxic and capable of loading and release DOX. Drug loaded NPs exhibited significant enhanced inhibition of mitochondria function in breast cancer cells during short periods (12 h) compared to free DOX. Although the expected pH responsive behaviour was not observed for the in vitro drug release model, NPs with histamine functionalization demonstrated partly endo-lysosomal escape property, in particular for those with 50% histamine modification. Intracellular tracking of NPs revealed that they could escape from endo-lysosomes and relocate DOX into mitochondria and the nuclei.
In paper VI, lipoprotein like NP systems were developed by incorporating Saposin A, phospholipids and selected hydrophobic cargos. Such systems were shown to have promise as drug delivery platforms and to serve as NP based vaccine stabilizers.
List of papers:
I. Yvonne Hed, Yuning Zhang, Oliver C.J. Andren, Xianghui Zeng, Andreas M. Nyström, Michael Malkoch. Side-by-side comparison of dendritic-linear hybrids and their hyperbranched analogs as micellar carries of chemotherapeutics. Journal of Polymer Science part A: Polymer Chemistry, 2013, 51, 3992-3996.
Fulltext (DOI)
View record in Web of Science®
II. Xianghui Zeng, Yuning Zhang, Andreas M. Nyström. Endocytic uptake and intracellular trafficking of bis-MPA-based hyperbranched copolymer micelles in breast cancer cells. Biomacromolecules, 2012, 13, 3814-3822.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Christian Porsch, Yuning Zhang, Åsa Östlund, Peter Damberg, Cosimo Ducani, Eva Malmström, Andreas M. Nyström. In vitro evaluation of non- protein adsorbing breast cancer theranostics based on 19F-polymer containing nanoparticles. Particle & Particle Systems Characterization, 2013, 30, 381-390.
Fulltext (DOI)
View record in Web of Science®
IV. Christian Porsch, Yuning Zhang, Cosimo Ducani, Francisco Vilaplana, Lars Nordstierna, Andreas M. Nyström, Eva Malmström. Toward unimolecular micelles with tunable dimensions using hyperbranced dendritic-linear polymers. Biomacromolecules, 2014, 15, 2235-2245.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Yuning Zhang, Pontus Lundberg, Maren Diether, Christian Porsch, Caroline Janson, Nathaniel A. Lynd, Cosimo Ducani, Michael Malkoch, Eva Malström, Craig J. Hawker, Andreas M. Nyström. Histamine-functionalized copolymer micelles as a drug delivery system in 2D and 3D models of breast cancer. Journal of Materials Chemistry B, 2015, 3, 2472-2486.
Fulltext (DOI)
View record in Web of Science®
VI. Jens Frauenfeld, Robin Löving, Yuning Zhang, Lin Zhu, Caroline Jegerschöld, Fatma Guettou, Per Moberg, Christian Löw, Andreas M. Nyström, Henrik Garoff, Pär Nordlund. A multi-functional nanoparticle system based on a small human protein. [Manuscript]
I. Yvonne Hed, Yuning Zhang, Oliver C.J. Andren, Xianghui Zeng, Andreas M. Nyström, Michael Malkoch. Side-by-side comparison of dendritic-linear hybrids and their hyperbranched analogs as micellar carries of chemotherapeutics. Journal of Polymer Science part A: Polymer Chemistry, 2013, 51, 3992-3996.
Fulltext (DOI)
View record in Web of Science®
II. Xianghui Zeng, Yuning Zhang, Andreas M. Nyström. Endocytic uptake and intracellular trafficking of bis-MPA-based hyperbranched copolymer micelles in breast cancer cells. Biomacromolecules, 2012, 13, 3814-3822.
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Christian Porsch, Yuning Zhang, Åsa Östlund, Peter Damberg, Cosimo Ducani, Eva Malmström, Andreas M. Nyström. In vitro evaluation of non- protein adsorbing breast cancer theranostics based on 19F-polymer containing nanoparticles. Particle & Particle Systems Characterization, 2013, 30, 381-390.
Fulltext (DOI)
View record in Web of Science®
IV. Christian Porsch, Yuning Zhang, Cosimo Ducani, Francisco Vilaplana, Lars Nordstierna, Andreas M. Nyström, Eva Malmström. Toward unimolecular micelles with tunable dimensions using hyperbranced dendritic-linear polymers. Biomacromolecules, 2014, 15, 2235-2245.
Fulltext (DOI)
Pubmed
View record in Web of Science®
V. Yuning Zhang, Pontus Lundberg, Maren Diether, Christian Porsch, Caroline Janson, Nathaniel A. Lynd, Cosimo Ducani, Michael Malkoch, Eva Malström, Craig J. Hawker, Andreas M. Nyström. Histamine-functionalized copolymer micelles as a drug delivery system in 2D and 3D models of breast cancer. Journal of Materials Chemistry B, 2015, 3, 2472-2486.
Fulltext (DOI)
View record in Web of Science®
VI. Jens Frauenfeld, Robin Löving, Yuning Zhang, Lin Zhu, Caroline Jegerschöld, Fatma Guettou, Per Moberg, Christian Löw, Andreas M. Nyström, Henrik Garoff, Pär Nordlund. A multi-functional nanoparticle system based on a small human protein. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Nyström, Andreas
Issue date: 2015-05-07
Rights:
Publication year: 2015
ISBN: 978-91-7549-939-0
Statistics
Total Visits
Views | |
---|---|
Development ...(legacy) | 675 |
Development ... | 309 |
Total Visits Per Month
October 2023 | November 2023 | December 2023 | January 2024 | February 2024 | March 2024 | April 2024 | |
---|---|---|---|---|---|---|---|
Development ... | 3 | 0 | 1 | 0 | 1 | 2 | 5 |
File Visits
Views | |
---|---|
Thesis_Yuning_Zhang.pdf(legacy) | 777 |
Thesis_Yuning_Zhang.pdf | 273 |
Yuning_Final_kappa.pdf(legacy) | 1 |
Top country views
Views | |
---|---|
Germany | 199 |
United States | 160 |
Sweden | 108 |
China | 80 |
South Korea | 30 |
Denmark | 25 |
Russia | 17 |
United Kingdom | 14 |
Iran | 9 |
Ireland | 8 |
Top cities views
Views | |
---|---|
Ashburn | 48 |
Kiez | 33 |
Beijing | 29 |
Seoul | 25 |
Stockholm | 22 |
Ballerup | 20 |
Woodbridge | 12 |
Umeå | 11 |
Dublin | 8 |
Nanjing | 8 |