Development of Transformable Nanotherapeutics for Cancer Therapy

Show simple item record Zhang, Feng 2021-11-26T05:55:43Z 2021-12-05 2021-11-26T05:55:43Z 2021-12-15
dc.identifier.uri URN:ISBN:978-951-51-7781-0
dc.description.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. en
dc.description.abstract -, fi
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Helsingin yliopisto fi
dc.publisher Helsingfors universitet sv
dc.publisher University of Helsinki en
dc.relation.isformatof URN:ISBN:978-951-51-7780-3
dc.relation.isformatof Helsinki: University of Helsinki, 2021, Doctoral thesis. 2342-3161
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dc.title Development of Transformable Nanotherapeutics for Cancer Therapy en
dc.type.ontasot Doctoral dissertation (article-based) en
dc.type.ontasot Artikkeliväitöskirja fi
dc.type.ontasot Artikelavhandling sv
dc.ths Santos, Hélder
dc.ths Hirvonen, Jouni
dc.ths Zhang, Hongbo
dc.opn Coffer, Jeffery
dc.type.dcmitype Text
dc.contributor.organization University of Helsinki, Faculty of Pharmacy en
dc.contributor.organization Doctoral Programme in Drug Research en
dc.contributor.organization Helsingin yliopisto, farmasian tiedekunta fi
dc.contributor.organization Lääketutkimuksen tohtoriohjelma fi
dc.contributor.organization Helsingfors universitet, farmaceutiska fakulteten sv
dc.contributor.organization Doktorandprogrammet i läkemedelsforskning sv
dc.type.okm 317 Farmasia fi
dc.type.okm 317 Farmaci sv
dc.type.okm 317 Pharmacy en
dc.type.publication doctoralThesis

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