Synthesis And Application Of Multimodal Imaging-Guided Multifunctional Nanomaterials For Collaborative Treatment Of Pancreatic Cancer

Nanomaterial-based pancreatic cancer treatment has received wide attention and got rapid development in the past few years.The major challenges include the poor combination of diagnosis and therapy,the difficulty in targeting therapy and the unsatisfactory antitumor efficiency,which are accompanied with a great risk of relapse and metastasis.In addition,on account of the virtue of tumor microenvironment(TME),such as hypoxia,slight acidity and highly concentrated hydrogen peroxide(H₂O₂),developing a simple and effective strategy to build a multi-functional nanomedicine that holds TME stimuli-responsive theranostic capacities has shown their great advantages.Researches have proved that the imaging and therapeutic effects of nano-therapeutic agents can be profoundly influenced by their composition,charge and particle size.In this thesis,we have designed three nanoplatforms based on the concept of multifunctional and stimulus-responsive theranostics and used them for the diagnosis and treatment of pancreatic cancers.In particular,we focus on constructing the multi-functional nanoplatforms of multi-modal imaging-guided photothermal therapy combined with gene therapy or photodynamic therapy.Eventually,the performance of nano-diagnostic reagents have been optimized during the theranositc of cancers.The mainprogresses are addressed as follows:1.In this work,a positive charged lipid bilayer membrane(DODAB/DOPE)is coated on reduced graphene oxide@gold nanostar(rGO@AuNS)to produce a new gene/photothermal synergetic therapeutic agent:rGO@AuNS-DODAB/DOPE.In addition,the cross-linking of folic acid on the surface of rGO@AuNS-DODAB/DOPE can specifically identify cancer cells with high surface expression of folic acid receptors(FR).Folic acid can greatly improve the targeting ability of the nanomaterials and the diagnostic performance of photoacoustic and photothermal imaging through receptor-mediated endocytosis.Moreover,the photothermal and gene(targeting G12V mutant K-Ras)synergistic therapy shows outstanding anticancer efficacy for pancreatic cancer tumor bearing mice,and it is noteworthy that the treatment groups have anti-liver metastasis of pancreatic cancer.2.With ascorbic acid(AA)as the reductant and prussian blue analogue as the shape controlling seed,the liposome-coated prussian blue@gold nano-flower multifunctional carrier(Lipo-PBA-Au)was synthesized through a facile one-step synthesis strategy.Then the RGD peptide with targeting ability was modified on the active site of liposome surface to prepare Lipo-PBA-Au-RGD(LPBGD)with a positive charge,which can carry siRNA and effecively enter pancreatic cancer cells with high expression of?v?₃integrin receptors.When irradiated by 808 nm laser,the light energy is converted into heat,and the photothermal therapy starts.Meanwhile,since the temperature is higher than the phase transition temperature of the lipid,more siRNA can be released due to the change of phase state.More tumor cells can be efficiently killed and the tumor recurrence can be inhibited through gene synergy photothermal therapy.In addition,LPBGD has been used in diagnosis in vivo owing to the excellent photoacoustic,CT and photothermal imaging diagnostic capabilities.3.An nanomaterial complex(UCNP@TA/Fe)composed of upconversion nanoparticle coated with tannic acid(TA)and Fe³⁺is synthesized through a facile strategy at room temperature.The negativity of nanomaterial complex elevates the loading capacity of photosensitizer(PS)and the doping of Fe³⁺,which leads to the activity of catalase with excellent performance to catalyze H₂O₂ in cancer cells to generate O₂.Therefore,the tumor hypoxia is alleviated and the PDT efficacy is improved.In addition,the(4-Carboxybutyl)triphenylphosphonium bromide(TPP)targeting mitochondria and the RGD peptide possessing high affinity to integrin receptor of?v?₃ are linked onto the surface of UCNP@TA/Fe through amination reaction and Michael addition reaction,respecitively.As a result,the nanomaterials carring photosensitizer can readily enter ROS-sensitive organelle-mitochondria.The PTT and PDT can be simultaneously trigered by merely one laser at 808 nm.Moreover,the UCNP@TA/Fe can be used as diagnostic reagent of multimodal imaging to guide the treatment of pancreatic cancer with the hypoxic TME by photoacoustic(PA),nuclear magnetic resonance(MR),photothermal(PT)and upconversion(UC)fluorescence with satisfactory results.