Magnetic Iron Based Functionalized Nanoparticles For Tumor Diagnosis And Treatment

Tumors threatened human’s health seriously,and caused most deaths in the world.With the development of nanotechnology,nanomaterials have overcome the shortcomings of traditional tumor diagnosis and treatment methods with their inherent advantages,and provide new and effective diagnosis and treatment methods.In this paper,we constructed EGFR-targeted polypeptide modified iron oxide nanoparticles（Fe₂O₃-pep）,monocyclic peptides（MCP）(the CXC chemokine receptor 4（CXCR4 antagonist）functionalized MnIO NPs（MnIO-MCP）and peptide-functionalized manganese-doped iron oxide nanoparticle-based fluorescence turn-on sensing platform（MnIO@pep-FITC）.Further,based on the above nanoparticle,the study were carried on tumor targeted imaging,diagnosis-treatment integration and enzyme activity detection.Finally,the application of magnetic iron-based nanoparticles in the field of tumor diagnosis and treatment were carefully conducted,the main the results obtained are as follows:1.Fe₂O₃-pep tumor-targeting nanoparticles were successfully prepared by using Fe₂O₃-PEG and EGFR targeting peptide（CGEHGAMEI）.The study have shown that Fe₂O₃-pep have good colloidal stability,low toxicity,and enriched in liver.It also can be used as a T2WI contrast agent(r₂=51.3 mM^-1S^-1),and has better tumor targeting than Fe₂O₃-PEG.This study initially explored the application of targeted magnetic iron oxide nanoparticles in tumor imaging,which paved the way for the following research of this thesis.2.Mmultifunctional nanoparticles（MnIO-MCP）were successfully synthesized by bioconjugation of the monocyclic peptides（MCP,the CXC chemokine receptor 4（CXCR4）antagonist）with manganese/iron oxide nanoparticles（MnIO NPs）for active-tumor targeting T1-weighted and T2-weighted（T1-T2）dual-modal magnetic resonance imaging（MRI）-guided biological-photothermal therapy（Bio-PTT）.MnIO-MCP displays both T1-weighted and T2-weighted MR contrast abilities(r₁=13.1 mM^-1S^-1;r₂=46.6 mM^-1S^-1,and r₂/r₁=3.56),allowing generation of enhanced T1-T2 dual-modal MRI.The MnIO-MCP exhibits reasonable photothermal conversion efficiency(28.8%with 200μg mL^-1MnIO-MCP in H₂O)under 808 nm NIR laser irradiation,endowing them with the capacity for PTT of tumor.Moreover,MnIO-MCP affords the strong tumor targeting and inhibition of cancer cell growth by the interactions of MCP with over expressed CXCR4 in tumor.We demonstrate that MnIO-MCP can accumulate in MCF-7 tumors as high as～15.9%ID g^-1at1 h after intravenous injection into mice with the aid of an external magnetic field（MF）,creating opportunity for complete eradication of tumor by T1-T2 dual-modal MRI-guided Bio-PTT.3.A fluorescence turn-on nanosensor（MnIO@pep-FITC）for detecting trypsin activity in vitro and in vivo were obtained through covalently immobilizing FITC modified peptide substrate of trypsin（pep-FITC）on manganese-doped iron oxide nanoparticle（MnIO NP）surface via a polyethylene glycol（PEG）crosslinker.The conjugation of pep-FITC with MnIO NP results in the quenching of FITC fluorescence.After trypsin cleavage,the FITC moiety is released from the MnIO NP surface,leading to a remarkable recovery of FITC fluorescence signal.Under the optimum experimental conditions,the recovery ratio of FITC fluorescence intensity is linearly dependent on the trypsin concentration in the range of 2 to100 ng mL^-1in buffer and intracellular trypsin in the lysate of 5×10²to 1×10⁴HCT116cells mL^-1,respectively.The detection limit of trypsin is 0.6 ng mL^-1in buffer or 359 cells mL^-1HCT116 cell lysate.The MnIO@pep-FITC is successfully employed to noninvasively monitor trypsin activity in the ultrasmall（4.9 mm³in volume）BALB/c nude mouse-bearing HCT116 tumor by in vivo fluorescence imaging with an external magnetic field assistance,demonstrating that it has excellent practicability.In conclusion,the functionalized iron-based nanoparticles exhiubite good biocompatibility and improve the efficiency of tumor imaging,treatment and detection.With the aid of an external magnetic field,radical treatment of subcutaneous tumors and imaging of ultra-small tumor can be achieved,which provides new ideas and methods for tumor diagnosis and treatment.