The Facile Preparation Of Novel Manganese-Based Multifunctional Nanoparticles And Their Application In Cancer Diagnosis And Therapy

Cancer nanotheranostic technology is a method that integrates the dual function of tumor diagnosis and treatment into a single nano-system.It has great application in multi-modal imaging,imaging-guided tumor therapy and real-time monitoring of tumor prognosis.Among those nanotheranostic systems,manganese-based multimodal imaging(magnetic resonance(MR)imaging/ultrasound(US)imaging)guided photothermal therapy(PTT)or photodynamic therapy-synergized immunotherapy shows excellent outcomes because of their precise lesion localization post tumor treatment,sensitive parameter adjustment during tumor therapy,and real-time monitoring after tumor treatment.However,these versatile manganese-based nanotheranostic systems often require complicated preparation processes and stringent reaction conditions,and hold poor reproducibility and low yields,which limits their clinical application.On the other hand,even if a small number of tumor theranostic nanosystems can be prepared by some efficient methods,their biosafety and theranostic functions may also be not satisfactory.Collectively,the extremely-efficient synthetic preparation and high-performance theranostic functions and high biosafety of the current theranostic nanosystems seem unable to be simultaneously generated.The first part of this thesis firstly reported a new and universal biomineralization strategy.The albumin was used as a template to in situ integrate oxidative polymerization and biomineralization to efficiently and easily synthesize multifunctional manganese-based theranostic nano-systems,which avoided the low efficiency of post-modification.A series of biomineralized polymers and manganese dioxide hybrid nanoparticles(PMHNs)were obtained through the polymerization of amino-group-based small molecule including dopamine(DA),pyrrole(PY),diaminopyridine(DP),reduction of potassium permanganate(KMnO4),and subsequently formation of manganese dioxide(MnO2)nanoparticles in albumin templates.The representative nanoparticle,PMHN-DA8,showed extremely efficient multimodal imaging(magnetic resonance imaging and ultrasound imaging)contrast ability(the longitudinal relaxation rate(r1)can reach 38.14 mM-1 s-1,about 9 times of the medical small molecule contrast agent,Magnevist)and excellent PTT tumor efficacies(the photothermal conversion efficiency reached 47.1%).In addition,they also exhibited ultra-high biocompatibility and renal clearance,leading to less systemic toxicity.Taken together,these multifunctional nanotheranostic agents showed great potential for imaging-guided PTT treatment of different tumors.In the second part,in order to solve the problem that polyphenolic polymers with highly efficient theranostic performance and high biosafety cannot be efficiently obtained,we have adopted the above-mentioned novel biomineralization method to produce them by changing polymerizable monomer.The amino group-containing monomer was replaced by a hydroxyl group-containing polyphenol monomer.Epicatechin,albumin(BSA),PEG,and potassium permanganate were used as the raw materials to efficiently synthesize polyphenol oligomers based theranostic nanoparticle,which integrated with MnO2 in it.Such manganese-based hybrid polyphenolic nanoparticles(BME)not only showed high-performance multifunctional magnetic resonance(MR)imaging(subcutaneous tumor imaging,liver metastasis imaging and kidney imaging)contrasting ability(longitudinal relaxation rate r1 up to 30.01 mM-1 s-i),but also could function as a highly efficient photothermal(PTT)agent in tumor treatment(the photothermal conversion efficiency>40%).In addition,they were also highly biocompatible with rapid renal clearance.Furthermore,in the third part,focusing on the problems that the existing nanovaccines cannot acessed with both high-efficient preparation and high-performance theranostic functions and high biosafety,the above-mentioned new biomineralization was still used.We employed one-pot method to synthesize a minimalist manganese-based multifunctional nanovaccine,OMD,which was purely composed of polydopamine(PDA),ovalbumin(OVA)and manganese dioxide(MnO2).Since it simultaneously contained PDA(a photothermal agent)and OVA(a common model antigen),the nano-vaccine OMD could obtain tumor PTT ability,and in the meantime stimulate the in vivo immune response to achieve tumor immunization.In addition,due to its MnO2,OMD can not only promote the tumor-associated macrophage to tumor suppressor phenotype(M1)polarization in the tumor microenvironment(TME),but also can act as a nanoimmune vaccine,which effectively prevented tumors from genesis and development in vivo.It can also be used as a highly effective MR imaging enhancer(longitudinal relaxation rate ri up to 31.07 mM-1s-1)to improve the contrast ability of MR imaging to monitor tumor and metastasis treatment in real time.In general,this thesis takes the form "one method,three applications" to lay a new foundation for the research of the multi-functional theranostic nanoplatforms with "three highs" characteristics(high-efficient preparation,high-efficient theranostic,and high-performance biosafety).