Biomimetic Responsive Nano-drug Delivery System And The Application Research

As one of the deadliest diseases,the tumor has brought serious mental pressure and economic burden to patients and society.Although chemotherapy,radiotherapy,and surgery are the main methods of tumor therapy,their low selectivity and severe side effects can lead to tumor recurrence and metastasis.Biomimetic responsive nanomaterials have shown great potential application prospects in the fields of drug delivery and release,sensing,and bioimaging,due to their unique properties of chemical/physical changes in response to external stimuli（such as pH,light,temperature,enzymes,magnetism,etc.）and the advantages of good biocompatibility,better targeting,and not easily cleared by the immune system.Based on this,this thesis designed and synthesized a series of biomimetic responsive nanomaterials for drug delivery and tumor therapy.The main research contents are as follows:1.pH-responsive nanoreactors for tumor starvation therapy and cascaded anaerobic activated chemotherapyIntratumoral glucose depletion-induced starvation therapy was an important tumor therapy strategy,but its therapeutic effect was limited by the toxicity of materials,non-specificity,and the anaerobic microenvironment within the tumor.In this work,a biomimetic pH-responsive nanoreactor was constructed based on the pH-responsive metal-organic framework ZIF-8loaded the glucose oxidase（GOx）and the anaerobic activated prodrug AQ4N and further wrapped the cell membrane of the target tumor.The biomimetic nanoreactor was endowed with the advantages of homologous targeting,immune escape,and prolonged blood circulation time by the tumor cell membranes.Benefiting from these unique properties,the biomimetic nanoreactor was efficiently and selectively accumulated into target tumor cells and released GOx and AQ4N in an acidic environment.GOx quickly consumed endogenous glucose and oxygen,and the energy supply of tumor cells was cut off to realize starvation therapy.Meanwhile,the non-toxic prodrug AQ4N was activated into toxic chemotherapy drug AQ4 in the tumor anaerobic environment,and the exacerbated anaerobic environment enhanced its toxicity for chemotherapy.The synergistic effect of tumor starvation therapy and cascade-amplified anaerobic activated chemotherapy based on the biomimetic pH-responsive nanoreactor improved the tumor therapy effect.2.Light-responsive nanomedicine for ion channel therapy and chemotherapy of the tumorPrecise control of cellular ion channels provided new ideas for tumor therapy.The current challenge was how to non-invasively and efficiently regulate the function of cellular ion channels.In this work,biomimetic light-responsive nanomedicines were fabricated by black phosphorus quantum dot clusters and anaerobic activated prodrug AQ4N encapsulation in thermosensitive liposomes,which were modified with DBCO groups on the surface.The biomimetic light-responsive nanomedicines were immobilized to the cell surface via the glucose metabolism and a highly specific bio-orthogonal copper-free click chemistry reaction.The localization of nanomedicines on the cell surface was achieved through the fluorescence of AQ4N.Under near-infrared light irradiation,the anaerobic activated prodrug AQ4N was released from the liposomes along with the temperature increase of the black phosphorus quantum dot clusters.The TRPV1 channel on the tumor cell membrane was opened due to the local temperature increase increased on the tumor cell surface.A large amount of Ca²⁺flowed into the cell,resulting in mitochondrial Ca²⁺overloading and mitochondrial apoptosis.The open and close of ion channels in tumor cells were controlled by light,which not only precisely regulated the amount of Ca²⁺entering,but also effectively regulated the physiological functions of target cells.In addition,the released nontoxic prodrug AQ4N was activated within the tumor anaerobic environment for tumor chemotherapy.The biomimetic light-responsive nanomedicine provided a new strategy for tumor therapy by precisely regulating tumor cell ion channel therapy and chemotherapy.3.pH-and light-responsive cascade release platform for tumor therapy by mitochondrial dysfunctionMitochondria were not only the place of cell energy storage and supply,but also have a variety of important physiological functions.It was an effective way of tumor treatment by taking tumor cell mitochondria as the target of damage,inducing mitochondrial function damage and leading to apoptosis.In this work,a biomimetic cascade release platform was constructed by the ion channel targeting drug ABT-199 encapsulation in thermosensitive liposomes,doxorubicin hydrochloride（DOX）adsorption on the surface by electrostatic interaction,and a Fe-TA network coating layer with pH and photothermal responsive properties.In the acidic environment of the tumor,the Fe-TA complex moiety dissociated.DOX was released and the fluorescence recovered,realizing the localization of the tumor.Near-infrared light irradiation at the tumor site,liposome phase transition occurred and released ABT-199 due to the photothermal properties of the Fe-TA complex.The ABT-199 specifically recognized the Bcl-2 protein in the endoplasmic reticulum（ER）and destroyed the IP3R/Bcl-2 complex,leading to the opening of the inositol 1,4,5-triphase receptor（IP3R）channel on the ER.Furthermore,IP3R and the voltage-dependent anion channel protein（VDAC1）on the mitochondria were connected through the glucose-regulated protein 75（Grp75）to form a Ca²⁺-directed transport channel,which effectively improved the entry of Ca²⁺content into the mitochondria,leading to the mitochondrial dysfunction.In addition,the ROS generated by the Fenton reaction through the dissociated iron ions further disrupted the function of mitochondria to balance Ca²⁺concentration.The biomimetic pH-and light-responsive cascade release platform exacerbated mitochondrial dysfunction function through the synergistic effect of ROS and Ca²⁺overloading,which was a safe and efficient anti-tumor platform for development potential in tumor therapy.In this paper,biomimetic pH-responsive,light-responsive,pH-and light-responsive nanomaterials were successfully prepared.The efficiently killing of the tumor cell has been achieved based on different ways of tumor treatment,including starvation therapy,ion channel therapy,and the treatment of mitochondrial dysfunction.This work provided a new idea for the formulation of accurate and effective tumor treatment strategies and provided theoretical guidance for clinical tumor treatment.