The Construction Of Polyphenol-based Supramolecular Nanodrug And The Application In Tumor Treatment

Polyphenols are organic molecules containing multiple phenolic hydroxyl groups,which are widely found in natural plants.In recent years,polyphenols have attracted extensive attention because of the abundant species and good biomedical functions.However,polyphenols,as small molecules,generally have the disadvantages of low water solubility and bioavailability,as well as non-targeting,which greatly limit their further application in biomedical fields.To overcome these defects,researchers have prepared many nanomaterials to load polyphenols and improved the bioavailability.However,the low loading efficiency,non-targeting releasement,and the potential toxicity of the carriers still need to be refined.Therefore,it is important to develop non-carrier polyphenol-based supramolecular nanodrugs according to the molecular structural features of polyphenols,promising to overcome the disadvantages of low bioavailability and non-targeting of polyphenols.In this thesis,we chose three polyphenols,including（-）-Epigallocatechin gallate（EGCG）,dopamine（DA）,and apigenin（Ap）,to develop polyphenol-based supramolecular nanodrugs.The as-constructed polyphenol-based supramolecular nanodrugs are potentially applicable in the tumor imaging and therapy.In the second chapter,we designed EGCG-and L-arginine（L-Arg）-based self-delivery supramolecular nanodrugs（SDSNDs）,achieving apoptosis for tumor therapy induced by EGCG and NO gas therapy.Leveraging the abundant phenolic hydroxyl groups and active hydrogen of EGCG,L-Arg is linked with the assistance of formaldehyde through Mannich reaction.Moreover,thanks to the molecular framework characteristics of EGCG,the Mannich condensation products can further assemble into SDSNDs throughπ-πinteractions,enabling the self-delivery of L-Arg and EGCG.The covalent linkage between L-Arg and EGCG avoids premature leakage,significantly improving the half-life and bioavailability of L-Arg and EGCG in drug delivery.The guanidine group of L-Arg in the SDSNDs can produce NO in the presence of the over-expressed H₂O₂ in the tumor microenvironment（TME）,provoking the damage of mitochondria and DNA,thus apoptosis of tumor cells.Meanwhile,EGCG amplifies apoptosis and inhibits the proliferation of tumor cells.In animal experiments,SDSNDs achieved amplified apoptosis of tumors induced by NO combined with EGCG,demonstrating the great tumor inhibition efficiency.The great biosafety also exhibits the advantages of the polyphenol-based supramolecular nanodrug delivery system.In the third chapter,we designed copper ion and ruthenium complex co-doped polydopamine nanoparticles（Cu（II）/LRu/PDA NPs）for magnetic resonance（MR）and photoacoustic tomography（PAT）imaging-guided photodynamic and photothermal dual-mode therapy（PDT/PTT）.By virtue of the supramolecular interactions between LRu and the polyphenol framework of PDA,such asπ-πstacking and hydrogen bonding,LRu is loaded and endows the NPs with the ability to generate reactive oxygen species（ROS）with the irradiation of a 660 nm laser,realizing PDT.Because of the strong absorption in the near-infrared（NIR）region,PDA can not only generate heat for PTT under irradiation but also be used for photoacoustic tomography（PAT）imaging.Meanwhile,the coordinated Cu（II）with PDA facilitates T₁-weighted MR imaging.The in vivo experiments indicate that the Cu（II）/LRu/PDA NPs can accumulate in He La tumors with a retention rate up to 8.34%ID/g.MR/PAT imaging can clearly identify the location and boundary of the tumors,permitting precise guidance for phototherapy.Under the combined effect of PDT and PTT,a complete ablation of He La tumors is achieved.The current work provides an alternative nanoplatform for performing PDT/PTT dual-mode therapy,which can be further guided by MR/PAT imaging.In the fourth chapter,aiming at the unavailability of single valency polyphenols in forming metal-phenolic networks（MPNs）,we innovatively proposed a FeOOH-assisted preparation method for MPNs-based antitumor supramolecular nanodrugs.In this strategy,the key issue is to realize single valency polyphenols in forming MPNs.Taking Ap as an example,we facilitated the inextensible Fe³⁺-Ap complexes forming MPNs in the connection of FeOOH,thus preparing the Fe³⁺-Ap complexes coated FeOOH nanoparticles（FeOOH@Fe-Ap NPs）by utilizing the coordination between Fe³⁺and Ap,and the hydrophobic interaction between Ap molecules.Under the stimulation of TME,FeOOH@Fe-Ap NPs could release Fe²⁺and Ap,realizing ferroptosis and apoptosis for tumor combination therapy.In addition,FeOOH can act as a T₂-weighted magnetic resonance imaging contrast agent.In animal experiments,the GSH-responsive FeOOH@Fe-Ap NPs demonstrate a great effect of combined ferroptosis and apoptosis for tumor therapy.The current efforts provide an alternative strategy for constructing MPNs by exploiting single valency polyphenols,facilitating the construction and design of single valency polyphenol-based antitumor supramolecular nanodrugs.