Preparation Of Prussian Blue-based Nanodrug System And Applications In The Treatment Of Acute Myeloid Leukemia And Protection Against Liver Injury

Prussian blue nanoparticles show excellent biocompatibility,strong near-infrared absorption,and effective scavenging capacity of reactive oxygen species(ROS),which make their broad application prospects including drug delivery,tumor photothermal therapy and protection against oxidative stress-related diseases.Acute myeloid leukemia(AML)is a highly fatal hematologic malignancy.Chemotherapy remains the standard method in clinic.However,it still faced with bottleneck problems such as poor treatment effect,recurrence and metastasis.At present,developing nanodrug system that overcome physiological barriers such as blood circulation,tumor enrichment,cellular endocytosis and lysosome escape has become the main strategy to realize enhanced efficacy and reduced toxicity.CXCR4 and CD44 receptors are closely associated with AML recurrence and metastasis.Aiming for both the two targets and designing nanodrug system that comprehensively address the drug delivery barriers is important for improving AML treatment efficacy.In addition,given that combination of chemotherapy and photothermal therapy can avoid the limitations of monotherapy,the construction of nanodrug system with combination therapy property is crucial for enhancing AML treatment efficacy.Clinical studies show that anthracycline induced liver injury is a potential clinical complication in AML treatment,and its liver toxicity is mainly related to the overproduction of ROS.Thus,Prussian blue nanoparticles are expected to exert prevention effect on liver injury.Based on this,aiming to collaboratively play a role in drug encapsulation,long blood circulation,targeting capability,effective lysosomal escape and metastasis inhibition,we designed functional Prussian blue-based nanodrug system and evaluated the treatment effect of AML.In addition,we assessed Prussian blue nanocarriers protective effect against liver injury.The dissertation includes the following three parts:1.The study of CXCR4 and CD44 dual-targeted acid-sensitive Prussian blue nanodrug system(DNR-loaded E5/HA-PP-PBNPs)for AML highly effectively targeted therapy and metastasis inhibition.Prussian blue nanoparticles(PBNPs)were prepared by hydrothermal method.After acid-sensitive polyethylene glycol-polyethyleneimine copolymer(PEG-d-PEI),CXCR4 antagonistic peptide E5 and hyaluronic acid(HA)and daunorubicin(DNR)were adsorbed via electrostatic interaction and chemical methods,DNR-loaded E5/HA-PP-PBNPs was successfully prepared.The results showed that Prussian blue nanocarrier exhibited acid-responsive drug release behavior.Compared to the single-targeted nanodrug system,dual-targeted DNR-loaded E5/HA-PP-PBNPs could increase the cellular uptake of drugs,enhance the effect of promoting apoptosis of leukemia cells and inhibit leukemia cells migration and adhesion induced by bone marrow stromal cells.In addition,DNR-loaded E5/HA-PP-PBNPs could greatly inhibit the proliferation of leukemia cells in bone marrow and peripheral blood,reduce the liver and spleen metastasis and prolong the survival of AML mice,indicating their best therapeutic effect.Hence,DNR-loaded E5/HA-PP-PBNPs represent a promising strategy for AML treatment.2.The study of zwitterionic polymer modified hollow mesoporous Prussian blue nanoparticles(HMPBs(DNR+Ara C)@PEI-ZS-E5)for chemotherapy and photothermal combination therapy of AML.Firstly,hollow Prussian blue nanoparticles(HMPBs)were prepared and subsequently loaded with DNR and cytarabine(Ara C).PEI,zwitterionic sulphobetaine and acrylic acid copolymer(ZS)and E5 were next modified onto the surface of the nanoparticles to fabricate HMPBs(DNR+Ara C)@PEI-ZS-E5.The results showed that nanocarriers exhibited excellent photothermal conversion efficiency,photothermal stability,anti-protein adsorption ability,photothermal-responsive drug release behavior and leukemia cells target ability.Compared to single chemotherapy group,chemotherapy and photothermal combination therapy could increase the proportion of apoptosis of leukemia cells and aggravate DNA damage,suggesting combination therapy can enhance the efficacy of AML.Hence,hollow Prussian blue-based chemotherapy and photothermal combination therapy show valuable research value for improving therapeutic effect of AML.3.The study of the multienzyme activity of Prussian blue nanoparticles as drug carrier and their protective effects on anthracycline induced liver injury.We studied the effect of Prussian blue nanocarriers on hepatocyte oxidative stress injury by establishing DNR induced liver injury model.The results showed that Prussian blue nanocarriers showed catalase,superoxide dismutase and peroxidase-like activities.Prussian blue nanocarriers could reduce AML12 cells oxidative stress levels and inhibit their apoptosis induced by DNR.In addition,Prussian blue nanocarriers alleviate liver oxidative stress level in model mice,increase the activity of antioxidant enzymes,reduce inflammatory cells infiltration,and up-regulate the expression of Nqo1 and HO-1 antioxidant genes,implying their protection effect on liver injury induced by DNR.Prussian blue nanocarriers provides new options for the prevention of ROS-related disease.