Designed Fabrication Of Multifunctional Nanocomposites For Tumor Phototherapy

Phototherapy has been widely studied due to its spatio-temporal responsiveness and non-invasiveness.The anti-tumor effects are achieved by activating the phototherapy agents that enriched in the tumor site under the irradiation of light with a specific wavelength to generate heat or reactive oxygen species?ROS?.However,current phototherapy agents show limited therapeutic effects due to the drawbacks such as shallow penetration depth of excitation light,lack of tumor selectivity,and non-durable treatment effects.In recent years,nanomaterials with special optical properties have been widely used in the development of phototherapy nanoagents.With the development of nanotechnology in the field of pharmaceutics,the fabrication of multifunctional nanocomposites by assembling functional nanocomponents can improve the tumor selectivity of phototherapy,ensuring the high efficiency and safety of the treatment.Through the integration of different therapeutic agents,the combination of tumor phototherapy with other therapeutic modalities can be realized for an enhanced therapeutic effect.Nowadays,the development of multifunctional nanocomposite phototherapy agents has become one of the hot spots in the research of tumor phototherapy.The template method has been widely applied in the fabrication of multifunctional nanocomposites.The nanocomposites based on organic polymeric soft templates can exhibit dynamically changed morphology and structure,which is conducive to realize the tumor microenvironment responsive treatment.In this thesis,we used tumor pH-responsive polymeric photosensitizer ligands as soft templates for the assembly of upconversion nanoparticles through hydrophilic and hydrophobic interactions to fabricate the near-infrared triggered and tumor pH-responsive photodynamic nanoagents?PPNs?.PPNs were assembled under normal physiological conditions?pH 7.4??¹20 nm?with negative surface potential.The photosensitizers were aggregated inside and self-quenched due to the fluorescence resonance energy transfer.Once PPNs entered the tumor microenvironment?pH 6.5?,pH-responsive ligands were protonated,and the surface potential turned positive,leading to the enhanced affinity with negative cells and increased cellular uptake.In this condition,PPNs began to expand due to the electrostatic repulsion force?¹50 nm?,which increased the distance between photosensitizers,resulting in the recovery of photodynamic activity.PPNs were completely disassembled into well-dispersed nanoparticles?³0 nm?after entering the lysosomes of the tumor cell?pH 5.5?.Upon 980 nm laser irradiation,the fluorescence emitted by upconversion nanoparticles further triggered the photosensitizers to generate ROS and induce cell death.Besides,upconversion fluorescence could also be used for imaging-guided laser irradiation.In vivo anti-tumor experiments showed that PPNs could effectively inhibit tumor growth.Moreover,in the 7 mm pork tissue covered deep tumor model,PPNs also exhibited efficient deep PDT effect.In addition,using inorganic nanomaterials hard templates is easy to assemble functional nanocomponents into multifunctional nanocomposites with specific heterostructure for multi-mode treatments.In the second part,mesoporous silica nanoparticles?MSN?were further used as hard templates,and ultra-small sized iron oxide nanoparticles?IONP?with catalytic and magnetic resonance imaging?MRI?contrast abilities were decorated on the surface of MSN.Gold nanorods?Au?were embedded inside as photothermal conversion agents to form the multifunctional photothermal agent?Au@MSN@IONP?.The hydrodynamic diameter of Au@MSN@IONP was 109 nm,which is suitable for tumor passive targeting.It showed strong absorption in the near-infrared region.Upon 808 nm laser irradiation,the temperature of the suspension increased rapidly,indicating the good photothermal conversion performance of Au@MSN@IONP.Moreover,Au@MSN@IONP exhibited excellent catalytic ability and T₂-weighted MRI contrast ability.Based on these outstanding functions,Au@MSN@IONP was used for the treatment of triple-negative breast cancer?TNBC?,which currently has no effective treatment.It is reported that ferroportin is markedly reduced in TNBC cells as compared with normal breast epithelial cells,resulting in high iron retention.The abnormal iron metabolism provides an opportunity for combating TNBC via iron-dependent production of ROS by Fenton reaction.Upon 808 nm laser irradiation,the gold nanorods could generate heat to induce the increase of hydrogen peroxide level in TNBC cells,thus providing the substrate for iron-catalyzed Fenton reaction to produce hydroxyl radicals that killing the cell.By comparing the cytotoxicity in different cell lines,it was found that cells with low ferroportin expression were more susceptible to Au@MSN@IONP based therapy.According to the proteomic analysis,Au@MSN@IONP could promote the apoptosis of TNBC cells by activating Bcl-2 family protein and inhibiting PI3K/Akt/FoxO signaling pathway.Moreover,the tumor location and the optimal irradiation time window could be determined by in vivo MRI.Consequently,precise in vivo orthotopic TNBC ablation is achieved by the synergistic effect between photothermal effect and Fenton reaction.Besides,there was no significant difference in body weight,pathological staining of main organs and blood biochemical indexes,indicating the good biocompatibility of Au@MSN@IONP.In this thesis,a series of multifunctional nanocomposite phototherapy agents were synthesized by physical,chemical and pharmaceutical methods,which exhibited the selectivity and efficiency in tumor phototherapy:?1?Nanocomposite photodynamic agents based on the assembly of pH-responsive polymeric photosensitizer ligands and upconversion nanoparticles was prepared for PDT.The photodynamic activity of photosensitizer molecules was controlled by the structural change of nanocomposite photodynamic agents at tumor microenvironment pH value,leading to pH-responsive NIR-triggered deep PDT;?2?Multifunctional nanocomposite photothermal agent based on the assembly of the ultra-small iron oxide nanoparticles with MR imaging and catalytic abilities and mesoporous silica-coated gold nanorods with good photothermal conversion ability was synthesized for MR imaging-guided photothermal/Fenton reaction combined therapy of TNBC.By utilizing the vulnerability of iron efflux in TNBC cells,Fenton reaction is accelerated by the elevation of intracellular H₂O₂ induced by photothermal effect,resulting in a highly efficient TNBC-specific therapy.The strategies presented in this thesis for the fabrication of multifunctional nanocomposite phototherapy agents would provide new ideas and theoretical basis for the development of phototherapy nanoagents in the future clinical tumor treatment.