The Application Of Dual-targeted Thermo-sensitive Magnetoliposomes In Multi-modal Imaging And Triggering Drug Release For Precise Tumor Treatment Research

Nanotechnology,which has a history of about forty years,has an unparalleled impact on chemistry,materials science and medicine,especially for providing a novel way of thinking and important means for diagnosis and treatment of malignant tumors which is one of three major ills in the world.Compared with the conventional antitumor drug therapy regimen with insufficient drug concentration at target site,low curative effect,large side effect,and single model,the new therapeutic mode of nanomaterials loaded traditional antineoplastic drugs has obvious advantages,which could improve the targeting ability of traditional antineoplastic drugs,reduce the damage to normal tissues,and realize multi-mode diagnosis and treatment integration.Therefore,the precise administration of antitumor drugs to specific tumor sites has become a hot spot and difficult point in the research of nano drug delivery system in recent years.In this study,methotrexate-modified(MTX)thermo-sensitive magnetoliposomes(MTX-MagTSLs)with both photo-thermo and magnetocaloric-induced drug release were designed.In particular,oleic acid modified magnetic nanoparticles(MNPs)and lipophilic fluorescent dye Cy5.5 were encapsulated in the bilayers of methotrexate-modified thermo-sensitive liposomes,then the doxorubicin(Dox)hydrochloride was loaded by using ammonium sulfate gradient loading method.In this nano drug delivery system,methotrexate and oil-soluble magnetic nanoparticles could be applied to folate receptor bio-targeting and magnetic targeting.Meanwhile,fluorescent dye Cy5.5 and magnetic nanoparticles can not only realize fluorescence imaging and magnetic resonance imaging(MRI)to determine the degree of aggregation of nanoparticles in the tumor site,but also provide a specific laser radiation region for rapid release of anticancer drug under an alternating magnetic field(AMF).Evaluate the prepared methotrexate-modified thermo-sensitive magnetoliposomes loaded doxorubicin hydrochloride comprehensively through characterizing the morphology,size,Zeta potential,and magnetic characterization of nanoparticles,determining the cell toxicity,intracellular drug uptake,as well as investigating the pharmacokenitics,bio-distribution,body toxicity and anti-tumor efficacy in vivo.The experimental results showed that the magnetic nanoparticles prepared by a high temperature decomposition method had a size of about 4 nm,and the methotrexate-modified thermo-sensitive magnetoliposomes prepared by thin-film dispersion method had good superparamagnetism,the diameter was 107.5 ±1.19 nm,the Zeta potential was 16.8±1.2 mV,which showed good stability with no significant changes in one week.The phase change temperature(Tm)of thermo-sensitive liposomes was around 45?,the release quantity of doxorubicin at 24 h under 45? is twice that under 37?.Small animal imaging and magnetic resonance imaging in vivo proved that the prepared nanomaterials could be used in fluorescence imaging and magnetic resonance imaging T2 negative imaging well.In vitro cytotoxicity,cell uptake,drug distribution in vivo,and tumor therapy results showed that methotrexate-modified thermo-sensitive magnetoliposomes had superior targeting ability on cervical cancer cells(HeLa)and HeLa tumor-bearing mice.At the same time,the thermal absorption of nanoparticles excited by alternating magnetic field and near infrared light simultaneously was 4.2 times of that of exciting by alternating magnetic field or near-infrared light separately,which could reach the phase change temperature of the designed nanoparticles quickly within 5 minutes,achieving the rapid release of drug in the region of the tumor,and realizing the precision of the antitumor treatment ultimately.In summary,the methotrexate-modified multifunctional thermo-sensitive magnetoliposomes nanoparticles prepared in this paper could achieve dual-mode targeting incorporating biological and magnetic targeting,dual-mode imaging including fluorescence imaging and magnetic resonance imaging,and dual-mode drug release under magnetocaloric and photothermal treatment,which improve the targeting,controlled release,and multiple imaging capabilities of the traditional administration.It is regarded as a significant step in the process of realizing precise tumor diagnosis and treatment integration,providing a reference for the relevant research in this field.