MRI Guided Nano Drug Delivery System For Tumor Theranostics

Cancer is a major public health problem in most countries and is the second leading cause of death in the world.At present,chemotherapy is still one of the most effective ways to treat cancer in clinic.However,the traditional chemotherapy is difficult to distinguish between cancer cells and normal cells,causing serious side effects to patients.Moreover,because that the conventional chemotherapeutic drugs cannot be traced in the body,their distribution in the tumor tissue cannot be known in real time.Therefore,they cannot provide timely feedback for the clinical effectiveness of the drug.This is also one of the main reasons why personalized treatment of cancer cannot be achieved.Many scientists believe that this is the major problem in the current clinical chemotherapy of tumor,which need to be urgently addressed by an effective technology.Theranostics,which integrate cancer diagnosis and cancer treatment functions,providing an effective and convenient technique for the personalized treatment of cancer.Nanotechnology has provided a new multifunctional platform for the early diagnosis and accurate treatment of cancer and other serious diseases.Nanoparticles(NPs)have been widely used as a carrier for tumor diagnosis and treatment.Therefore,this paper aims to prepare Poly(L-?-glutamyl-glutamine)-Paclitaxel-Diethylenetriaminepentaacetic acid-Gd(PGG-PTX-DTPA-Gd)NPs and Fe3O4@SiO2@mesoporous SiO2/Doxorubicin-(Gd-DTPA)-Polyethylene glycol-RGERPPR(Fe3O4@Sio2@mSio2/DOX-(Gd-DTPA)-PEG-RGE)NPs magnetic resonance imaging(MRI)guided nano drug delivery system for tumor theranostics,to achieve real-time tracing chemotherapy in vivo and timely feedback drug clinical effect.In Chapter 1,a brief introduction of the research significance of this subject,the current incidence of cancer and mortality at home and abroad,the main treatment of cancer,the current status of the tumor theranostics,the subject of research ideas and research content were introduced.In Chapter 2,the preparation and characterization of PGG-PTX-DTPA-Gd NPs nano drug delivery system for tumor theranostics were introduced.Poly(L-y-glutamyl-glutamine)-paclitaxel(PGG-PTX),as a model polymer,was chemically conjugated with Gd-DTPA(Gd-diethylenetriaminepentaacetic acid),a T1-contrast agent of MRI,to prepare a Gd-DTPA-conjugated PGG-PTX(PGG-PTX-DTPA-Gd)delivery system used for tumor theranostics.PGG-PTX-DTPA-Gd can be self-assembled to NPs in water with a z-average hydrodynamic diameter about 35.9 nm.The 3 T MRI results confirmed that the relaxivity of PGG-PTX-DTPA-Gd NPs(r1 = 18.98mM-1S-1)was increased nearly 4.9 times compared with that of free Gd-DTPA(r1 = 3.87 mM-1S-1).In Chapter 3,the in vitro and in vivo evaluation of PGG-PTX-DTPA-Gd NPs nano drug delivery system for tumor theranostics were introduced.In vitro cell uptake and cytotoxicity assays of NCI-H460 cells(human non-small cell lung cancer cells)confirmed that the presence of Gd-DTPA had essentially no effect on cell uptake and cytotoxicity of PGG-PTX NPs.The in vivo fluorescence imaging results showed that PGG-PTX-DTPA-Gd NPs could be accumulated in the tumor tissue of NCI-H460 lung cancer animal model by enhanced permeability and retention(EPR)effect,which was similar to PGG-PTX NPs.The MRI results showed that compared with free Gd-DTPA,PGG-PTX-DTPA-Gd NPs showed significantly enhanced and prolonged signal intensity in tumor tissue,which should be attributed to the increased relaxivity and tumor accumulation.PGG-PTX-DTPA-Gd NPs also showed effective antitumor effect in vivo.Furthermore,the Hematoxylin and Eosin(H&E)staining and TdT-mediated dUTP Nick-End Labeling(TUNEL)assay proved that the NPs produced obvious cell apoptosis in tumor tissue.In Chapter 4,the preparation and characterization of Fe3O4@SiO2@mSiO2/DOX-(Gd-DTPA)-PEG-RGE NPs nano drug delivery system for tumor theranostics were introduced.A tumor-penetrating peptide RGERPPR(RGE)modified,Gd-DTPA conjugated,and doxorubicin(DOX)loaded Fe3O4@SiO2@mSiO2 nanoparticle drug delivery system(Fe3O4@SiO2@mSiO2/DOX-(Gd-DTPA)-PEG-RGE NPs)was prepared for tumor theranostics.The Fe3O4@SiO2@mSiO2/DOX-(Gd-DTPA)-PEG-RGE NPs showed a z-average hydrodynamic diameter of about 90 nm.The 3 T MRI results confirmed the relaxivity of the Fe3O4@SiO2@mSiO2/DOX-(Gd-DTPA)-PEG-RGE NPs(rn = 6.13mM-IS-I,r2 = 36.89 mM-1S-1).In Chapter 5,the in vitro and in vivo evaluation of Fe3O4@SiO2@mSiO2/DOX-(Gd-DTPA)-PEG-RGE NPs nano drug delivery system for tumor theranostics were introduced.The Fe3O4@SiO2@mSiO2/DOX-(Gd-DTPA)-PEG-RGE NPs showed a pH-sensitive DOX release profile in vitro.The in vitro cellular uptake and cytotoxicity assays on U87MG glioblastoma cells confirmed that the conjugation of RGERPPR played a significant role in increasing the cellular uptake and cytotoxicity of the NPs.The near-infrared fluorescence in vivo imaging results showed that the NPs could be significantly accumulated in the U87MG tumor tissue,which should resulted from the mediation of the tumor-penetrating peptide RGERPPR and its neuropilin-1(NRP-1)has specific over-expression on tumor blood vessels and U87MG cells.The MRI results showed that the NPs offered a T1-T2 dual mode contrast imaging effect which would lead to more precise diagnosis.Compared with unmodified NPs,the RGE-modified NPs showed significantly enhanced the MR imaging signal intensity in tumor tissue and the antitumor effect,which should be also attributed to the tumor penetrating ability of RGERPPR peptide.Pharmacokinetic study and bio-distribution study results showed that the RGE-modified NPs showed significantly increased tumor accumulation and penetration by the mediation of RGERPPR.Compared with unmodified NPs,the RGE-modified NPs showed significantly prolonged circulation time in blood and significantly enhanced accumulation in tumor tissue,which should also be attributed to the tumor penetrating ability of RGERPPR peptide.Furthermore,the H&E staining and TUNEL assay proved that the NPs produced obvious cell apoptosis in tumor tissue.In Chapter 6,the conclusion and prospect were introduced.In this paper,these results indicated that PGG-PTX--DTPA-Gd NPs and Fe3O4@SiO2@mSiO2/DOX-(Gd-DTPA)-PEG-RGE NPs are effective MRI guided nano drug delivery systems for tumor theranostics,and should have a potential value in personalized treatment of tumor.