TY - JOUR A1 - Bleul, Regina A1 - Thiermann, R. A1 - Marten, G.U. A1 - House, M.J. A1 - St. Pierre, T.G. A1 - Häfeli, U.O. A1 - Maskos, M. T1 - Continuously manufactured magnetic polymersomes - a versatile tool (not only) for targeted cancer therapy N2 - Micromixer technology was used to prepare polymeric vesicles (Pluronic® L-121) dual loaded with the anti-cancer drug camptothecin and magnetic nanoparticles. Successful incorporation of the magnetic nanoparticles was confirmed by transmission electron microscopy. Dynamic light scattering measurements showed a relatively narrow size distribution of the hybrid polymersomes. Camptothecin polymersomes reduced the cell viability of prostate cancer cells (PC-3) measured after 72 h significantly, while drug-free polymersomes showed no cytotoxic effects. Covalent attachment of a cancer targeting peptide (bombesin) as well as a fluorescent label (Alexa Fluor® 647) to the hybrid polymersomes was performed and specific cell binding and internalization were shown by flow cytometry and confocal microscopy. Relaxometry measurements clearly demonstrated the capacity of magnetic polymersomes to generate significant T2-weighted MRI contrast and potentially allow for direct monitoring of the biodistribution of the polymersomes. Micromixer technology as an easy, fast and efficient way to manufacture hybrid polymersomes as theranostic drug delivery devices is a further step from basic research to personalized medicine. KW - Polymersomes KW - Pluronics KW - Drug delivery KW - Theranostics KW - Micro mixer PY - 2013 DO - https://doi.org/10.1039/c3nr02190d SN - 2040-3364 SN - 2040-3372 SP - 1 EP - 9 PB - RSC Publ. CY - Cambridge AN - OPUS4-28847 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - CONF A1 - Bleul, Regina T1 - Magnetic Polymersomes - A Versatile Tool for Targeted Cancer Therapy T2 - E-MRS Spring Meeting CY - Strasbourg, France DA - 2013-05-26 PY - 2013 AN - OPUS4-28784 LA - deu AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - CONF A1 - Bleul, Regina A1 - Thiermann, Raphael A1 - Saatchi, K. A1 - Häfeli, U.O. A1 - Maskos, M. ED - Parak, W.J. ED - Osinski, M. ED - Yamamoto, K. T1 - Multifunctional nanocarriers for biomedical applications N2 - Polymeric vesicles (Pluronic® L-121) loaded with magnetic nanoparticles (MNP) and an anti-cancer drug (camptothecin) were prepared continuously in a micro mixing device. Characterization by TEM confirmed the successful incorporation of the MNP and DLS measurements showed a relatively narrow size distribution of the hybrid polymersomes. A very high drug loading of camptothecin (100 µg/ml in the polymersome formulation) was reached and a drug release study of loaded magnetic polymersomes has shown a sustained camptothecin release over several days. Carboxylation of Pluronic® L-121 was performed and enabled a further surface functionalization with bombesin, a 14 amino acid peptide, which binds specifically to the GRPR (gastrin releasing peptide receptor). This receptor is often overexpressed in tumor cells (e.g., human prostate cancer cells) and therefore a suitable target for cancer treatment. An additional fluorescence label with Alexa Fluor® 647 allow tracking of the polymersomes e.g., in cell experiments. Relaxivity measurements to evaluate the potential of magnetic polymersomes as MR contrast agent for in vivo imaging are in progress. T2 - Colloidal nanocrystals for biomedical applications VIII CY - San Francisco, CA, USA DA - 22.02.2013 KW - Polymersomes KW - Vesicles KW - Block copolymers KW - Pluronics KW - Drug delivery KW - Micro mixer PY - 2013 SN - 9780819493644 DO - https://doi.org/10.1117/12.2008194 N1 - Serientitel: Proceedings of SPIE – Series title: Proceedings of SPIE VL - 8595 SP - 85951N-1 EP - 85951N-9 AN - OPUS4-28488 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - CONF A1 - Bleul, Regina T1 - Magnetic Polymersomes - Multifunctional Carriers for Biomedical Applications T2 - Magnetic Carrier Meeting CY - Minneapolis, MN, USA DA - 2012-05-21 PY - 2012 AN - OPUS4-27315 LA - deu AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - CONF A1 - Bleul, Regina T1 - Functional Polymersomes - Potential Multi-Tool for Targeted Cancer Therapy T2 - NanoBiomed 2012 - Nanomaterials for Biomedical Technologies CY - Frankfurt am Main, Germany DA - 2012-03-06 PY - 2012 AN - OPUS4-27310 LA - deu AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - CONF A1 - Bleul, Regina T1 - Functional Polymersomes - Potential Multitool for Targeted Cancer Therapy T2 - Nanomaterials for Biomedical Technologies CY - Frankfurt am Main, Germany DA - 2012-03-06 PY - 2012 AN - OPUS4-25690 LA - deu AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - JOUR A1 - Bleul, Regina A1 - Bachran, D. A1 - Thiermann, Raphael A1 - Bertin, Annabelle A1 - Fuchs, H. A1 - Maskos, Michael T1 - Probing polymersome-protein and -cell interactions: influence of different end-groups and environments N2 - Developing polymersomes for drug delivery purposes requires a deeper understanding of their behavior in physiological environment. We performed the self-assembly and in-situ loading of polybutadiene-block-polyethyleneoxide (PB-b-PEO) polymersomes in a continuous process using micromixers. Varying the length and end-groups of the starting block copolymer allows us to control the polymer membrane thickness and surface functionalities (hydroxyl or carboxylic acid), required to realize a further coupling with specific cell targeting ligands. To get a deeper understanding of these polymersomes in physiological environment, we studied the cellular response (HeLa cells) in presence of various polymersomes, and showed by cytotoxicity tests the relative biocompatibility of the systems. Flow cytometry experiments at 4?°C in PBS buffer showed a different behavior of hydroxyl-functionalized vesicles compared to carboxylic acid-functionalized vesicles. On the contrary cell binding in DMEM medium supplemented with 10% FCS was almost completely blocked with both kinds of polymersomes. Protein adsorption measurements by dynamic light scattering confirmed that protein binding occurs in all cases, which apparently influences the particle-cell interaction. This study contributes towards a deeper understanding of polymersomes in biological environment and further investigations will help us to design highly effective polymersomes for in vitro as well as in vivo applications. KW - Drug delivery KW - End-group functionality KW - Particle-cell interaction KW - Physiologic environment KW - Polymersomes KW - Protein adsorption PY - 2011 DO - https://doi.org/10.1002/masy.201100042 SN - 1022-1360 SN - 0258-0322 SN - 1521-3900 VL - 309/310 IS - 1 SP - 134 EP - 140 PB - Wiley-VCH Verl. CY - Weinheim AN - OPUS4-25246 LA - eng AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - CONF A1 - Bleul, Regina T1 - Polymers in Biomedicine: Molecular Structure and Material Charakteristics T2 - Jahrestagung Deutsche Gesellschaft für Biomaterialien CY - Giessen, Germany DA - 2011-11-10 PY - 2011 AN - OPUS4-24935 LA - deu AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - CONF A1 - Bleul, Regina T1 - Probing Polymersome-Protein and -Cell Interactions: Structural Characterization and In Vitro Studies T2 - Bio-Nano Responses Conference CY - Essen, Germany DA - 2011-09-11 PY - 2011 AN - OPUS4-24465 LA - deu AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - CONF A1 - Bleul, Regina T1 - Probing Polymersome-Protein and -Cell Interactions: Structural Characterization and In Vito Studies T2 - Advanced Functional Polymers for Medicine 2011 CY - Enschede, Netherlands DA - 2011-06-15 PY - 2011 AN - OPUS4-23897 LA - deu AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER - TY - THES A1 - Bleul, Regina T1 - Herstellung, Charakterisierung und Funktionalisierung polymerer Nanopartikel und Untersuchung der Wechselwirkungen mit biologischen Systemen N2 - Die Nanomedizin beschäftigt sich unter anderen mit der Frage, wie sich die Behandlung gefährlicher Krankheiten effizienter und sicherer gestalten lässt, deren konventionelle Therapie oftmals mit schweren Nebenwirkungen einhergeht. Die Vision ist, ein theranostisches Wirkstoffträgersystem zu schaffen, das seinen therapeutischen Cargo sicher an den Wirkort transportiert, dort freisetzt und gleichzeitig in Echtzeit verfolgt werden kann, um die Therapie individuell anzupassen. Die Grundlage für die erfolgreiche Entwicklung eines Wirkstoffträgersystems bilden Untersuchungen zum Verhalten von nanopartikulären Substanzen in physiologischer Umgebung. Im Rahmen der vorliegenden Arbeit wurden polymere Nanopartikel unterschiedlicher Morphologie durch die kontrollierte Selbstorganisation amphiphiler Blockcopolymere hergestellt, charakterisiert und auf ihre Wechselwirkungen mit menschlichen Zellen und Serumproteinen untersucht. Dazu wurde eine Studie zur Geometrie- und Größenabhängigkeit der Zytoxizität von nanoskaligen Kugel- und Zylindermizellen sowie Vesikelstrukturen durchgeführt. Des Weiteren wurde das Agglomerationsverhalten von verschiedenen polymeren Nanopartikeln in Anwesenheit von Serumproteinen untersucht. Mit Hilfe eines Mikromischer-basierenden Verfahrens gelang es, kontinuierlich sehr einheitliche Polymervesikel herzustellen und diese in situ mit unterschiedlichen Komponenten zu beladen - unter anderem mit dem Wirkstoff Camptothecin sowie einer hohen Dichte an hydrophoben Eisenoxid-Nanopartikeln. Diese wirkstoffbeladenen Hybridvesikel zeigten in vitro im Vergleich zum freien Wirkstoff eine erhöhte zytotoxische Wirksamkeit gegen die Krebszelllinie PC-3. Nach einer Funktionalisierung mit einem krebszellspezifischen Targeting-Peptid und einer zusätzlichen Fluoreszenzmarkierung wurde mit Hilfe der Durchflusszytometrie und konfokalen Laser-Scanning-Mikroskopie eine rezeptor-spezifische Zellaufnahme in PC-3-Krebszellen demonstriert. Messungen zur magnetischen Charakterisierung bestätigten zudem die potenzielle Anwendung magnetischer Polymervesikel als MRT-Kontrastmittel wie auch als Tracer für das Magnetic Particle Imaging (MPI). Kontinuierlich hergestellte, wirkstoffbeladene, magnetische Polymervesikel erfüllen somit viele Grundvoraussetzungen für ein theranostisches Wirkstoffträgersystem und bieten weitere Entwicklungsmöglichkeiten im Hinblick auf Magnetfluid-Hyperthermie, magnetisches Targeting oder eine durch ein Magnetfeld induzierte Wirkstofffreisetzung. N2 - One of the main goals of nanomedicine is to improve the treatment of hazardous diseases whose conventional therapy often has serious side effects. The vision is to create a theranostic drug delivery system which is capable of safely transporting therapeutic cargo through the body to a targeted site of disease at which point the drug is released. Furthermore, it is desirable to track the carrier in real time which would allow for a personal adjustment of the therapy. Studies on the behavior of nanoparticulate substances in a physiological environment form the basis for the possibility to successfully develop a drug carrier system. In the present work, polymeric nanoparticles with different morphologies were prepared by the controlled self-assembly of amphiphilic block copolymers. The nanoparticles were subsequently characterized and their interactions with human cells and serum proteins investigated. A cytotoxicity study with spherical and cylindrical micelles as well as vesicular structures was carried out and showed a dependency of cytotoxic effects on the geometry and size of the nanoparticles. The agglomeration behavior of various polymeric nanoparticles in the presence of serum proteins was also studied. Highly uniform polymeric vesicles were continuously manufactured in a micromixer based device and in situ loading with different components was performed. In this way, dual loaded vesicles with the anticancer drug camptothecin and a high amount of hydrophobic iron oxide nanoparticles were produced. When tested in vitro, these drug-loaded vesicles showed an increased cytotoxic activity against the cancer cell line PC-3 when compared to the free drug. Specific cellular uptake in PC-3 cancer cells was demonstrated with flow cytometry and confocal laser scanning microscopy after functionalization with a cancer cell specific targeting peptide and an additional fluorescent label. Magnetic characterization of the iron oxide-loaded vesicles also confirmed the potential application as MRI contrast agents and as tracers for magnetic particle imaging (MPI). Continuously manufactured, drug-loaded, magnetic polymeric vesicles thus fulfill many prerequisites for a theranostic drug carrier system and provide opportunities for further developments in the field of magnetic fluid hyperthermia, magnetic targeting or magnetic drug release. T3 - BAM Dissertationsreihe - 133 KW - Selbstorganisation KW - Nanomedizin KW - Wirkstoffträgersystem KW - Krebstherapie KW - Theranostik PY - 2015 UR - https://nbn-resolving.org/urn:nbn:de:kobv:b43-5134 VL - 133 SP - 1 EP - 238 PB - Bundesanstalt für Materialforschung und -prüfung (BAM) CY - Berlin AN - OPUS4-513 LA - deu AD - Bundesanstalt fuer Materialforschung und -pruefung (BAM), Berlin, Germany ER -