Hypoxia And PH Dual-responsive Nanoprobes For Precision Imaging And Treatment Of Tumours

Tumourigenesis,growth and metastasis are closely related to the internal and external environment in which the tumour cells are located,which includes not only the structure,function and metabolism of the tumour tissue,but also the intrinsic environment(nuclear and cytoplasmic)of the tumour cells themselves,which is known as the tumour microenvironment.The tumour microenvironment is a complex and evolving entity that is generally characterised by both hypoxia and weak acidity.At the same time,the tumour microenvironment has long been a key and central aspect of tumour research,and is important for understanding the processes of tumour development,progression and metastasis,as well as for the diagnosis,prevention and prognosis of tumours.In this thesis,nanomaterials that are both hypoxic and weakly acidic in response to the tumour microenvironment are rationally designed to accurately image the tumour microenvironment and to treat the tumour region under the indication of fluorescence.The details of the study are as follows:1.A shuttle-type nucleic acid nanomaterial capable of sensing subtle changes in oxygen concentration and pH in tumor microenvironment and normal tissues was designed.The material takes advantage of the ability of exosomes themselves to shuttle freely in vivo and the bilayer membrane st ructure of exosomes,and uses exosomes as carriers in combination with self-assembled pendant-type nucleic acid tetrahedral probes labeled with cholesterol for the purpose of circulating detection in vivo.In the pendant nucleic acid tetrahedral probe,the cytosine-rich i-motif sequence serves as a key region for pH response.The fluorophores ROX and Cy5 are used as motifs indicating pH and oxygen concentration in the tumor microenvironment,respectively,in which the black hole quencher 2(BHQ2)acts as a quencher and as a hypoxia response element.The positions of the three motifs around the i-motif are rationally designed to perceive the difference between pH and oxygen concentration in the microenvironment and in the normal region.2.A multifunctional fluorescent nanomaterial that is dual-regulated by hypoxia and pH in tumor microenvironment with integrated therapeutic ability of dark toxicity and photothermal therapy was constructed.The material uses mesoporous silica coated on the surface of gold nanorods as a carrier,and the pH-responsive fluorescent nanoprobe Cy-Cl-OH with dark toxicity is loaded into the mesoporous silica pore channel,whose fluorescence is quenched by the gold nanorods.Meanwhile,azobenzoic acid with an azoic bond was modified on the silica surface as the anoxia-responsive element.The benzene ring structure of azo benzoic acid can be bound to β-cyclodextrin polymer(β-CDP)by host-guest interaction on the silica surface,and this property allows β-CDP to act as a "gatekeeper" to prevent the non-specific release of the probe Cy-Cl-OH.When the probe enters the anoxic environment,the azo bond in the anoxia response element is broken and reduced to an amino group,and the "gatekeeper" β-CDP falls off the mesoporous silica surface,thus allowing the pH-responsive fluorescent probe Cy-Cl-OH to be released from the pore channel and emit fluorescence in response to the pH of the environment.The probe Cy-Cl-OH stimulates the intracellular production of reactive oxygen species(ROS),which causes cellular damage,while the gold nanorods can generate thermal therapy under near-infrared light irradiation to achieve the synergistic therapeutic effect of both,enabling the nanoplatform to effectively kill tumor cells.