Development of Transformable Nanotherapeutics for Cancer Therapy

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http://urn.fi/URN:ISBN:978-951-51-7781-0
Title: Development of Transformable Nanotherapeutics for Cancer Therapy
Author: Zhang, Feng
Contributor organization: University of Helsinki, Faculty of Pharmacy
Doctoral Programme in Drug Research
Helsingin yliopisto, farmasian tiedekunta
Lääketutkimuksen tohtoriohjelma
Helsingfors universitet, farmaceutiska fakulteten
Doktorandprogrammet i läkemedelsforskning
Publisher: Helsingin yliopisto
Date: 2021-12-15
Language: eng
URI: http://urn.fi/URN:ISBN:978-951-51-7781-0
http://hdl.handle.net/10138/336772
Thesis level: Doctoral dissertation (article-based)
Abstract: By the virtue of the divers physicochemical properties, nanomaterials have emerged as a powerful platform to improve the pharmacokinetic properties of drug molecules. Furthermore, in view that the created or constructed materials own the same size level of biomacromolecules, and can be endowed with various biochemical functions, nanotechnology has been treated as the most promising technology to develop smart therapeutics with flexible articifal controllability to innovate the current medicine. Generally, the anchor or the breakthrough point of these technologies depends on the nanomaterials-based drug delivery systems (DDS), which has been in tremendous development for more than thirty years. However, clinical transition of DDS are facing great challenges related to the insufficient targeting accumulation in the cells/tissues. The in vivo delivery of nanotherapeutics is a multi-stage process and needs to conquer multiple biological barriers. In this case, conventional DDS is not competent enough to cope with the various biological barriers. Thus, the transformable design of DDS with tunable surface properties in responsive to stimuli-signals at different barriers are in urgent need. In this thesis, the focus was on constructing DDS with different stimulus and functions to achieve the task-oriented NPs’ transformation, including surface charge inversion, sequential antifouling surface, in situ size modulation and multi-stage signal interaction. Firstly, it was fabricated a PSi DDS with receptor-mediated surface charge inversion. The negatively charged surface can convert into positive charged surface in response to cancer micro- environment, driven by the AS1411-nucliolin interaction. Secondly, it was modified the biotin- PEI nanoparticles with acrylates-ortho-nitrobenzyl-PEG5000, which further acted as the primary antifouling surface to prevent the formation of protein corona and avoid off-targeting effect. After UV-irradiation, the PEG surface can be cleaved to generate carboxyl group on the biotin- PEI surface, forming a secondary zwitterionic anti-fouling surface. This dual-antifouling modification can efficiently avoid protein adsorption on the NPs’ surface in human serum. Moreover, the secondary zwitterionic surface can guarantee the effective exposure of active targeting segments for improving cell uptake. Simultaneously, the reduced size facilitates deep tissue penetration of the NPs. Thirdly, it was constrcuted a photo-driven size tunable DDS, which can increase the size after tumor accumulation in situ to prolong the tumor retention time and also to improve cancer cell uptake. Finally, it was developed a multistage signal interactive system on NPs through integrating the Self-peptide and YIGSR peptide into a chimeric form, with a hierarchical signaling interface involving “don’t eat me” and “eat me” signals. This biochemical transceiver can act as both signal receiver for amantadine to achieve NP transformation and signal conversion, as well as the signal source with different signals by reversible self-mimicking. Throughout chemical and biological testing, it was demonstrated these designed DDS have efficient signal-induced transformation behavior and enhanced controllability of NP-cell interactions for improving the cancer therapeutic efficacy. Overall, this dissertation provides a new insight of targeting drug delivery and nano-tools to facilitate clinical transition of nanomedicines.-,
Subject: https://helsinki.zoom.us/w/65592727704?tk=VY7-LHcqmYuaYB3jZRdFd8if6hd7U9WCsmWavJD-o5E.DQMAAAAPRaGYmBZGSlVYNWk3ZlM4aVRmLURwSTFaZDNRAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA
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