Polydopamine-Based Multifunctional Nanosystems For Cancer Therapy

Development of theranostic nanoplatforms with precise disease diagnosis and efficient treatment have always been an important goal of modern medicine.In recent years,multifunctional diagnostic probes have drawn dramatic attentions,as its ability to recognize malignant tumor and enhance the treatment effect.Nanocarriers possess several advantages,such as surface paintability,high loading capacity,appropriate particle size,surface charge and long-circulation time and so on,which have much prospect in the preparation of multifunctional probes.However,it is still a great challenge for preparation such nanoprobes with excellent biocompatibility,as well as play its optimal performance.Polydopamine’s spectacular success can be attributed to its unique features,for example,strong adhesive properties,easy and straightforward functionalization,and biocompatibility.Polydopamine has been merged with various nanostructures that differ in size and nature,which has resulted in novel types of multifunctional nanomaterials that have recently been extensively exploited in nanomedicine and particularly in cancer therapy.Based on the advantages of functional polydopamine,we have developed series of new multi-functional nanosystem for biological diagnosis and treatment.The major contents are as follows:（1）We reported a general method for the preparation of stimuli-responsive multifunctional MOF nanoparticles using PDA as a functional interface that affords facile conjugation with molecular units of interest as well as excellent photothermal transduction efficiency.Different MOFs were used to illustrate the generality of this strategy.The stimuli-responsive multifunctional MOFs act as efficient Delivery vehicles for combined chemo-photothermal therapy that is responsive to tumor microenvironment.This approach can be implemented to design stimuli-responsive multifunctional MOFs from other functional molecules such as proteins,enzymes,and therapeutic nucleic acids for specific purposes.（2）Based on the metal-chelating activity of the catechol groups on PDAs,we developedasimplemethodtoprepareinorganic-organichybrid PDAs-MB-CAT-ZIF-8 multifunctional nanoparticles.When the ZIF-8-shelled PDA nanoparticles are delivered into the cytoplasm,the nanosystem is stimulated by intracellular lower pH condition,releasing MB and free catalase for H₂O₂ catalyzed generate of O₂.Thus,the nanosystem improve the efficiency of O₂-dependent photodynamic therapy.In addition,under 660 nm and 808 nm laser irradiation,this nanocarrier is capable of near-infrared photothermal therapy,enabling synergetic photodynamic-photothermal therapy in vivo.（3）Combining with the existing problems of siRNA,PDAs-ZIF-8 prepared in the previous chapter was used to delivery siRNA.This nanoparticles could significantly avoid the pre-leakage of siRNA before it arrived to the tumor sites,protect siRNA from enzymatic degradation during the blood circulation process and realize pH-sensitivity controlled release of siRNA.The cell experiments and in vivo experiments demonstrated that PDA-siRNA-ZIF-8 greatly improved the treatment effect of gene therapy and photothermal therapy.（4）Based on the study of the first three chapters,the DNAzyme-MnPDA nanosystem was developed by adsorption of a folate-labeled DNAzyme onto the surface of MnPDA for multimodal imaging-guided gene regulation and photothermal therapy.The delivery vehicle of MnPDA protects DNAzyme from intracellular degradation,supplies a cofactor source of Mn²⁺for DNAzyme catalysis,and exhibits excellent photothermal transduction efficiency.When the catalytic deoxyribozyme-MnPDA nanoparticles are specifically recognized by cancer cell and delivered into the cytoplasm,the nanosystem is stimulated by intracellular glutathione（GSH）,releasing DNAzyme and concentrated free Mn²⁺for catalytic cleavage of intracellular mRNA.Thus,the nanosystem improves cellular uptake efficiency,ensures in vivo stability,and improves catalytic efficiency for gene regulation.In addition,this vehicle is capable of near-infrared photothermal imaging（IR）,photoacoustic imaging（PAI）,and magnetic resonance imaging（MRI）,enabling multimodal imaging guided synergetic gene-photothermal therapy in vivo.（5）Based on the coordination nanoparticles（MnPDA）we prepared in Chapter 3,multiple nucleic acids were facilely modified onto the nanoparticles to obtain probe DNA modified MnPDA（hpDNA-MnPDA）.The theranostics nanoplatform was used for multiplexed analysis of cancer biomarkers and multimodal-imaging guided cancer therapy.In the presence of TK1 mRNA and c-myc mRNA,hpDNA will hybridize with the complementary target sequences resulting its release from hpDNA-MnPDA and the relative fluorescence signals recovery.Moreover,hpDNA-MnPDA nanoprobe take advantage of the inherently characteristics of MnPDA for cancer therapy,such as the contrast agent for infrared photothermal imaging,photoacoustic imaging and magnetic resonance imaging,as well as the therapeutic agent for photothermal therapy.