Construction Of Polydopamine-based Multifunctional Nanoplatform For Tumor Theranostic Applications

In view of the high incidence and refractory nature of tumors,there is an urgent practical need to develop excellent tumor diagnosis and treatment strategies.The nanoplatform-based tumor theranostic strategies are attracting more and more attention due to the excellent tumor specificity and easy functionalization.In this thesis,a series of polydopamine?PDA?-based nanoplatforms were constructed and characterized,and their performance in tumor theranostic was studied by in vitro and in vivo models.The detailed research contents are as follows:1.PDA nanoparticles?NPs?were prepared by the polymerization of dopamine monomer in alkaline medium.They were modified with polyethylene glycol,and then loaded with the photosensitizer IR820 and the magnetic resonance contrast agent Fe³⁺by?-?/electrostatic interaction and chelation,respectively.The products had excellent properties,and showed the abilities of magnetic resonance imaging,photoacoustic imaging,free radical generation and photothermal transformation,which were positively correlated with the NP concentration.In vitro cell experiments showed that the obtained NPs had good cytocompatibility and significant cellular internalization behaviors.Under laser irradiation,the final NPs can effectively produce heat and reactive oxygen species,causing tumor cell death.At 150 ppm,the rate of cell death reached to about 90%.This developed NPs show desirable theranostic performance,owning magnetic resonance imaging/photoacoustic imaging/photodynamic therapy/photothermal therapy abilities and showing potential in future tumor theranostic applications.2.A kind of drug-loaded PDA/dendrimer-gold nanocomposite were designed and constructed,which were consisted of the PDA core,the dendrimer-gold satellite,the polyethylene glycol chain shell,and the doxorubicin payload.PDA NPs had abundant surface chemical groups,which facilitated the payload of satellite NPs and chemical drugs.Meanwhile,PDA NPs had good biocompatibility and near-infrared?NIR?light response ability.The decorated satellite NPs can be released under the stimulation of the intratumoral acidic environment,penetrating into the deep site of tumor and realizing drug cascade delivery.Gold NPs with catalase-like activity catalyzed the decomposition hydrogen peroxide to produce oxygen,alleviating the hypoxia-induced drug-resistance.The loaded chemical drug doxorubicin can be released under the stimulation of heat,weak acid,and hydrogen peroxide,achieving photothermal-assisted chemotherapy.This developed nanocomposites had good stability,and the loaded satellite NPs and drug can be released under stimulation.The enhanced permeability and drug delivery behavior have been proved using3D cell spheroid and in vivo tumor models.Finally,effective tumor therapy has been realized under the guidance of photoacoustic/near-infrared fluorescence dual-mode imaging.This developed core-satellite-structured drug-loading PDA/dendrimer-gold NPs could significantly enhance the tumor therapeutic effect through the combination of photothermal effect,relieving hypoxia,enhancing permeability,and cascade delivery strategies,realizing photothermal-enhanced chemotherapy.3.Using PDA NPs as the carrier,glucose oxidase,bovine serum albumin,and iron phosphate NPs were successively coated and formed,finally forming a multifunctional nanoenzyme platform.Firstly,PDA can be used for photoacoustic imaging and photothermal therapy agent.Secondly,bovine serum albumin can improve the stability and biocompatibility of the nanoenzyme.Thirdly,glucose oxidase can catalyze glycolysis and consume glucose in the tumor region to produce gluconic acid and hydrogen peroxide,rebuilding tumor microenvironment and realizing starvation effect.At the same time,the expression of heat shock protein was inhibited in this low-glucose environment,which was beneficial for the development of PDA-mediated low-temperature photothermal therapy.Finally,the enhanced acidity can not only accelerate the degradation of iron phosphate to release Fe³⁺,but also enhance the reducibility of PDA.Through the dedox reaction between them,the sustainable supply of Fe²⁺with higher Fenton catalytic activity was realized to produce highly toxic hydroxyl radicals,finally achieving enhanced chemodynamic therapy.In vitro and in vivo experiments showed that this nanoenzyme had excellent stability and stimuli-responsive ability?such as NIR laser,acid,hydrogen peroxide,and glucose?,showed good glycolysis and Fenton catalytic capacity.Under the guidance of photoacoustic/near-infrared fluorescence/photothermal triple-mode imaging,starvation/low-temperature photothermal/enhanced chemodynamic triple-model therapy was developed for tumor synergistic treatment.This constructed nanoenzyme can provide a solid data support and research foundation for the design of excellent tumor theranostic nanoplatforms,and provide significance support for the construction of nanoplatform with tumor microenvironment response and regulation ability.