Authors:	Kurch, Sven Andreas
Advisor:	Tremel, Wolfgang
Title:	Mesoporous silica nanoparticle for drug delivery of cancer therapeutics
Online publication date:	25-Apr-2024
Year of first publication:	2024
Language:	english
Abstract:	The aim of the present work was to develop a drug delivery system (DDS) based on mesoporous silica, which enabled the transport and release of a highly toxic cytokine (TNF−) and small molecule drugs for cancer therapy. In cooperation with the University Medical Center in Mainz and the Collaborative Research Center 1066, a systematic investigation of the WTS via in vitro test up to in vivo experiments was possible. In addition to the transport of these active ingredients, the development of a protective system (gatekeeper) for the local release of the respective cargo inside cell was a research topic. Taking into account the drug-specific properties (stability, charge and size), the protective systems and the intracellular release mechanism were adapted accordingly. The first part of this work presents the establishment of mesoporous silica as carrier platform. The synthesis of the dendritic mesoporous silica nanoparticles (DMSN) with various pore size and particle diameter was possible through systematic analysis of the surfactant-directed polycondensation. In addition to reaction parameter control, a dual surfactant method for pore expansion is presented. Core- and surface functionalization of the DMSN introduced anchor groups for the protective system, fluorescent dyes for in vitro cell localization and intraparticular bridging molecules. Integration of disulfide and tetrasulfide functionalities in the silica network was able to modify the intracellular biodegradability of the carrier systems. In addition, a core shell particle - Fe3O4 embedded in a mesoporous silica shell - for possible magnetic separation from a protein-rich matrix is shown. The second part of the work deals with the encapsulation and shielding of the highly toxic cytokine TNF- Beromun, tasonermin) in vitro and in vivo with a pH-sensitive hyperbranched polyethylenimine (PEI)-hydrophilic polyethylenglycol (PEG) copolymer gatekeeper. First, the safe use of the DMSN on various cell lines and immune cells could be proven dose-dependent. Second, DMSN could attenuate the systemic toxicity of TNF- while maintaining its pleiotropic anti-tumor activity in vitro and in a 3D cell model, which efficiently mimics tumor architecture and microenvironment. Colloidal stability of the DDS was shown with dynamic light scattering in simulated body fluid, an outstanding property for in vivo applications. Final in vivo experiments with non-invasive optical imaging were able to investigate the biological distribution of the cytokine after subcutaneous administration. The last part of this work shows the development of a new DDS (DMSN and gatekeeper) for the transport of Doxorubicin and a novel dinuclear Cu(II)-complex cytostatic for cancer therapy. A dual responsive drug delivery system, utilizing pH and Redox trigger through a surface bound inclusion complex, blocking the pores. Imine bridged ferrocene stalks interacting with a cyclic sugar (ß-CD) to restrict drug diffusion. The complete quantification of the surface modulation/inclusion complex optimized the DDS; enhanced drug encapsulation and ensures gatekeeper attachment. First in vitro experiments with a squamous cell carcinoma (SCC) tumor model demonstrate the particle uptake and intracellular release of both drugs.
DDC:	540 Chemie 540 Chemistry and allied sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 09 Chemie, Pharmazie u. Geowissensch.
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-10225
URN:	urn:nbn:de:hebis:77-openscience-c891df80-a752-4f02-b904-049a751463b47
Version:	Original work
Publication type:	Dissertation
License:	In Copyright
Information on rights of use:	http://rightsstatements.org/vocab/InC/1.0/
Extent:	XIV, 15-179 Seiten ; Illustrationen, Diagramme
Appears in collections:	JGU-Publikationen