Preparation Of Magnetic Iron Oxide Nanocubes And Research On The Application In Cardial Disease

Cardiovascular disease(CVD)has become the leading cause of human mortality worldwide and myocardial infarction(MI)is the most common adverse event which has an urgent need for powerful diagnostic and therapeutic methods.MI is resulted from the occlusion of the blood flow to the heart due to a thrombus on a ruptured atherosclerotic plaque.The specific infarcted area undergoes ischemic necrosis and apoptosis.After MI,a large number of monocytes/macrophages are recruited,acting as protagonists of inflammation and tissue repair.However exaggerated inflammation may contribute to adverse remodeling and non-contractile scar formation,which ultimately ending up with heart failure(HF)and a poor prognosis.Based on the phenomenon that a massive of macrophages infiltrate into the infarcted area,using the macrophages to diagnose and treat MI will be an efficient strategy.Magnetic resonance imaging(MRI)plays an important role in CVD allowing comprehensive anatomic,functional assessment as its high spatio-temporal resolution,non-radiation and excellent security.Contrast agents are widely applied in the clinic aiming for a high tissue contrast to improve the diagnostic accuracy and reliability.Traditional Gd contrast agents cannot be uptaken by cells.However,Magnetic iron oxide nanoparticles have been reported as a new type of MRI contrast agents with significant magnetic effect,supparamagnetic,biocompatibility and ability to be uptaken by cells for imaing.Based on this pathology,the external magnetic field-induced and phosphatidylserine(PS)-presenting iron oxide nanocubes were used to establish a theranostic nanosystem.This nanosystem was powerful for MRI of acute MI and inhibited the inflammation mimicking apoptosis,which improved the adverse remodeling.This system realized diagnosis and theray at the same time.The study mainly includes the following five parts.1.Synthesis and characterization of magnetic iron oxide nanocubes(MIONs).MIONs with high magnetic properties,small sizes and good dispersion were synthesized by high temperature thermal decomposition method.2.Synthesis and characterization of PLA-PCB.Poly(lactide)(PLA)was synthesized by ring-opening polymerization(ROP)of lactide(LA)(cyclic dimer of lactic acid)promoted by 2-Hydroxyethyl 2-bromoisobutyrate as the initiator and tin(II)octoate(Sn(Oct)2)as catalyst.The low hydrophobic property can be promoted by the introduction of the zwitterionic poly(carboxybetaine)(PCB),which also gives the pH-sensitive material the ability to release drugs inside by escaping from the endosome/lysosomes via the proton sponge mechanism.3.Preparation and characterization of PP/PS@MIONs.After filtering and optimization,PLA40-PCB(PP)and PS were coated on nanocubes by the thin-film method to construct magnetic field responsive theranostic nanosystem.PP/PS@MIONs had a size range of 50.6 ± 7.8 nm showing a good water solubility,dispersity and good superparamagnetism.The final concentration of PS was 3 mM,Fe was 1 mg/mL and the magnetic relaxivity was 376.5 mM-1s-1.The MR imaging results in vitro suggested that PP/PS@MIONs could efficiently decrease the T2-weighted MRI signal intensity and reveal a great MR imaging ability.4.In vitro anti-inflammation activity of PP/PS@MIONs.Work was carried out based on the RAW 264.7 macrophages.The drug delivery system showed high safety and had no obvious toxicity on RAW 264.7 cells.PP/PS@MIONs could be engulfed by RAW264.7 cells within 2 h,and the uptaken was remarkably enhanced in the presence of PS.12 h after being uptaken,PP/PS@MIONs showed significant escape from the endosomes/lysosomes releasing the iron nanocubes and PS into cytoplasm.The retention of the nanocubes benefited MRI of macrophages while PS was thought to work with paracrine or autocrine.Then peritoneal macrophages were used to detect the anti-inflammation activity of PP/PS@MIONs.Results showed that PP/PS@MIONs could modulate the phenotypes of macrophages and presented good anti-inflammatory activity.5.In vivo anti-inflammation activity of PP/PS@MIONs.Work was carried out based on Lewis rats which underwent permanently occlusion of the left main coronary artery(LAD)with an intramural suture as MI model rats.Exposed to the external magnetic field,the theranostic nanosystem accumulated remarkably in infarcted area.With the target effect,PS interacted with PS receptors on macrophages.This indicated the improvement of accumulation and remarkable MR imaging ability.Under the influence of external magnetic field in MI rats,PP/PS@MIONs could decrease the adverse remodeling and promote angiogenesis and heart repair.In summary,a kind of safe and effective theranostic nanosystem for MI was developed to realize diagnosis and therapy integration successfully in this paper.This study provides a reference for the exploration of new diagnosing and anti-inflammatory therapy for MI.