Studies On Hollow Mesoporous Organosilicon Nanoparticles For Tumor Therapy And MRI Visualization

Magnetic resonance imaging(MRI)is one of the most widely used imaging modalities in clinical practice,owing to its non-invasive nature,high spatial resolution,good soft tissue contrast,and unrestricted tissue penetration.However,MRI contrast agents(CAs)still present significant challenges in building functional diagnosis and treatment platforms,because the negative impact of uncontrolled aggregation that occurs with drug-loading applications.Hollow mesoporous organosilicon nanoparticles(HMON)offers prominent possibilities for the loading of various diagnostic and therapeutic agents due to their tunable mesopores and unique cavity structure,and have shown promise in integrating imaging and therapeutic functions for precision MRI and efficient tumor treatment.However,the construction of their theranostic nanoplatforms also has many problems that need to be solved,including poor targeting,uncontrollable leakage,poor stability,and short blood circulation time.Therefore,this thesis constructs a series of novel theranostic nanoplatforms with the tumor microenvironment(TME)specific response based on HMON.The main research work is described as follows:(1)Firstly,MRI-enabled core/shell Fe3O4/Gd2O3 hybrid nanoparticles(FG)are cleverly used as intelligent pore switches of HMON for optimizing drug delivery and tumor-specific drug release.After fully encapsulating the chemotherapeutic drug doxorubicin(DOX)into the cavities of the HMON,the FG is stably anchored on the pore wall by electrostatic and hydrogen bonding,and then the RGD dimer(R2)with active tumor targeting function is coupled on the surface of HMON in order to prepare D@HMON@FG@R2.In vitro and in vivo results show that FG aggregated in D@HMON@FG@R2 can darken normal tissues,and the intratumorally released FG as a result of reducibility-triggered HMON degradation can brighten the tumor tissues,realizing the integration of high-contrast MRI with specific chemotherapy.(2)Then,a strategy of limited-space controlled aggregation is further developed for improving the drug loading capacity of MRI CAs,and overcoming the problems of easy aggregation of MRI CAs after drug loading and premature release of drugs loaded in HMON.Especially,ultrasmall gadolinium oxide nanoparticles(GO)or Gd poly(acrylic acid)macrochelate(GP)and DOX(D)are sequentially loaded into the cavity structure of HMON by exploiting the limited space of the HMON cavity,and consequently form limited aggregates.The successfully prepared GO@D@HMON and GP@D@HMON have good dispersion stability and exhibit ultra-high loading capacity of MRI CAs.TME-specific glutathione(GSH)can trigger HMON degradation and activates high-contrast T1 MRI of tumors,achieving enhanced chemotherapeutic efficacy and mitigating side effects on normal cells/tissues.In vitro and in vivo experiments have validated the universality of this strategy.(3)Finally,a strategy of Fenton reaction cycloacceleration initiated by remodeling the THE is proposed for MRI-guided high performance ferroptosis therapy of tumors.By using the hollow core of HMON as a nanoreactor for "in situ copper oxide nanodot(CON)growth",β-lapachone(LAP)and gallic acid-Fe3+(GF)coordination network are then sequentially incorporated into the pore and shell of HMON,and the resulting nanoparticles are conjugated with 4-(2-aminoethyl)benzenesulfonamide(ABS)and PEG via an amidation reaction to generate the CON-LAP-HMON@GF-ABS-PEG.This strategy is based on the inhibition of CAIX by ABS to enhance the acidity of TME,the catalytic cycle of Fe-Cu,and the LAP-mediated H2O2 supply to synergistically form the cycloacceleration of Fenton reaction/Fenton-like reaction,producing abundant reactive oxygen(ROS)and substantial lipid peroxide(LPO)accumulation.Meanwhile,the GF network detached from HMON has an improvement of relaxivities in response to the TME,which allows for monitoring of the progress of tumor ferroptosis therapy.In summary,three novel nanotherapeutic agents with TME responsiveness were successfully constructed in this work,all of which can be used for contrast-enhanced MRI-guided efficient antitumor therapy.However,the metabolic pathways and longterm biosafety of the nanotherapeutics in vivo are still to be systematically investigated,which is expected to provide the research foundation for their next clinical applications.