Construction Of Enzyme-Propelled Nanomotors Based On Cisplatin Prodrugs For Precise Cancer Therapy

Cancer has seriously harmed human health.Although cisplatin has shown excellent anti-tumor effects in chemical drug treatment,it still has significant side effects.Moreover,long-term use of cisplatin can lead to drug resistance,reduce treatment effectiveness,and limit its medical application.The prodrug molecule of cisplatin has small toxic and side effects,and can be reduced to the original drug for treatment in specific environments.Through new technologies,it can be used as a nano drug.Nanodrug delivery systems have unique advantages in maintaining drug activity,stability,and drug delivery.However,the complex microenvironment of tumors hinders drug delivery and its penetration into tumor sites.Therefore,improving the delivery of nano drugs to increase their accumulation in tumor sites and achieving deep penetration are key to cancer treatment.Nanomotor is a nano platform that can convert other energy into its own kinetic energy,showing great potential as a drug delivery system for cancer treatment.Among them,enzyme driven nanomotors have received considerable attention.Enzyme-triggered biocatalytic reactions typically occur in mild physiological environments,using substrates available in the physiological environment as fuel.Therefore,the development of enzyme driven micro/nano motors for tumor treatment has great application prospects.In this thesis,an enzyme driven nanomotor based on cisplatin with dual response was constructed for cancer treatment through a multimodal combination of chemotherapy,hunger,and photodynamic therapy.The main research contents are as follows:1)Construct an enzyme-driven nanomotor based on cisplatin.First,the cisplatin prodrug molecule with less toxic and side effects was prepared and used as the ZIF skeleton.Through a simple one-step strategy of encapsulating glucose oxidase(GOx),catalase(CAT)and dihydroporphyrin(Ce6),a natural enzyme-driven drug with p H and GSH dual response was designed GC6@c Pt ZIF Nano motor.The successful preparation of cisplatin prodrug was confirmed by nuclear magnetic resonance and mass spectrometry.The morphology and elemental composition of the nanomotor were characterized by transmission and elemental analysis,and its particle size was confirmed to be 70～120 nm.The enzyme activity and photodynamic determination of encapsulated enzyme and photosensitive molecule were carried out by ultraviolet,dissolved oxygen and paramagnetism,which verified that the ZIF framework of nanomotor was a good carrier for drugs and would not affect the activity of drugs in the cavity.The oxygen produced by cascade enzyme catalysis can not only be used as the driving force of nanomotor,but also be supplied to photosensitive molecules to produce singlet oxygen.Moreover,the movement of the nanomotor was observed under the microscope,which proved that it could self-drive in glucose solution using glucose as fuel and the movement speed was dependent on glucose concentration.2)The anti-tumor performance of nano-motor was evaluated.We verify the anticancer effect of nanomotors at the cellular and animal levels.Through a series of models such as Transwell and 3D cell ball,the advantages of nanomotor movement in cell uptake and tumor deep penetration are explored;Through experiments such as reactive oxygen species probe,mitochondrial membrane potential probe and cell death staining,the ability of nanomotor to kill cancer cells was explored.The results showed that the prepared nano-motor could use glucose in the biological environment as a fuel,and the ability of self-movement could promote cell uptake and achieve deep penetration of tumor.Because of various drugs loaded on it,it can produce a great number of reactive oxygen species,destroy mitochondrial membrane potential and damage its normal function.It can also further consume GSH,not only destroy the balance of oxidative stress in cells,but also reduce the combination of GSH and cisplatin,thus increasing the probability of cisplatin acting on DNA and enhancing the chemotherapy of cisplatin.It can also consume a large amount of nutrients needed by tumor cells to make them die.Subsequently,a mouse model was established to study the anti-tumor effect of the prepared nano-motor in vivo,and it was confirmed that its combined chemotherapy,starvation and photodynamic therapy had good anti-tumor effect.In addition,various biochemical indexes of the treated mice were evaluated to verify their excellent biological safety.