Preparation Of Acid Sensitive Magnetic Lipid Nanoparticles And Research On Tumor Targeting Imaging And Magnetic Induction Hyperthermia

Breast cancer is one of the malignant tumors that threaten women’s life and health in recent years.At present,the main clinical treatments for breast cancer include surgical resection,chemotherapy and radiotherapy.However,these traditional therapies have brought lots of side-effects including drug resistance and resistance,high tumor recurrence rate,low tolerance for patients and disruption of immune system balance.Therefore,seeking a safe and effective tumor"green therapy"is the top priority in the future clinical treatment of breast cancer.Currently,magnetic nanomaterials-mediated magnetic induction thermal effect is a new treatment method for breast tumors,which can selectively heat tumor tissue and cause tumor cell apoptosis without damaging normal tissue.It has the advantages of targeting,minimally invasive,low toxic and side effects and obvious curative effect,and will become one of the best strategies for tumor treatment.In order to develop a class of high-performance magnetic nanomaterials for tumor hyperthermia,an optimized thermal decomposition was firstly designed as follows.In a dibenzyl ether solvent with a high boiling point,iron acetylacetonate was used as the precursor,and the doped zinc and surfactants were subsequently adjusted.By adjusting the ratio of two surfactants oleic acid（OA）and oleylamine（OAm）,the high-performance zinc-ferrite nanoparticles with excellent magnetic properties in sizes of 10 nm,13 nm,16 nm,20 nm and 34 nm have been successfully prepared.The characterization of physical and chemical properties shows that the prepared nanoparticles have good monodispersity and regular morphology.Secondly,the oil-soluble 13 nm-sized zinc ferrite nanoparticles were firstly selected as the nano-magnetic core,and were further coated with egg yolk lecithin（E80）and PEG-phospholipids,such as amino-modified polyethylene glycol phospholipid（DSPE-PEG-NH₂）and cholesterol modified polyethylene glycol phospholipid（DSPE-PEG-CLS）through hydrophobic interactions.Subsequently,the Schiff base（SB）groups were connected to the second PEG layer of nanoparticles,and the acid-sensitive magnetic lipid nanoparticles（MNPs@CLS@SB）were finally obtained.By optimizing the preparation process conditions,it is found that the optimum addition amount of E80 is 11 mg,and the molecular weight of PEG is 5000,and the MNPs@CLS@SB prepared by ultrasonic disintegration method has better water solubility,stability and dispersibility.The construction of this functional MNPs@CLS@SB provides a prerequisite foundation for the subsequent realization of in vivo tumor diagnosis and treatment.In the field of in vivo imaging,the fluorescent probe indocyanine green（ICG）molecules were inserted in the lipid molecular layer of MNPs@CLS@SB,which played a key role in simultaneously dual-modal magnetic resonance imaging（MRI）and fluorescence imaging performance.By constructing a mouse mammary gland orthotopic subcutaneous transplantation breast tumor（4T1）model and administering MNPs@CLS@SB intravenously（dose:25 mg Fe/kg body weight）,combining MRI and fluorescence imaging can achieve the accuracy of the material in the tumor area diagnosis and positioning.Studies have found that MNPs@CLS@SB can be significantly enriched in tumor tissue areas within 24 to 48 hours,and has good resistance to macrophage phagocytosis and blood circulation,so as to achieve the purpose of targeting tumor tissues.The reason for its targeting effect may be that when MNPs@CLS@SB reaches the slightly acidic environment of the tumor,the acid-sensitive SB bond on the surface is broken and the CLS group contained therein is exposed,which increases the affinity of the probe with tumor cells and makes the probe The long-term retention of the needle in the tumor tissue also provides a basis for the subsequent use of tumor magnetic hyperthermia（TMH）.In the evaluation of magnetic material-mediated TMH,by designing an optimized tumor treatment strategy,mice are randomly divided into a physiological saline group,an alternating magnetic field group only,a preparation group only,and a preparation and an alternating magnetic field at the same time.In the group,mice were injected with tail vein injection of MNPs@CLS@SB once every four days（single dose:25 mg Fe/kg body weight）,and a16-day tumor magnetic induction hyperthermia（alternating magnetic field frequency:480k Hz,current:20 A）.The surface temperature of the mouse after hyperthermia was detected by a thermal imaging instrument,and it was found that the tumor surface hyperthermia temperature could reach 42°C or more;through the immunohistochemical test of the mouse body weight,tumor size,and histopathological section,it was found that MNPs@CLS@SB-mediated TMH effect can significantly induce tumor cell apoptosis,inhibit tumor angiogenesis,delay tumor metastasis,and ultimately control tumor growth.The longest survival time of mice can be extended to more than 40 days.The functional MNPs@CLS@SB designed in this paper can innovatively solve the problems of short circulation time in the body of nanomaterials,short retention time in tumor areas,and easy phagocytosis of normal tissues.It provides a new strategy for the development of multimodal imaging-guided tumor precision treatment.