Research On The Application Of Poly(styrene-maleic Anhydride)Nanosystems In The Fight Against Tumors And Novel Coronaviruses

Several attempts at nanocarriers have been made to overcome cellular barriers in intracellular drug allocation,which have important clinical significance in major public diseases,especially in tumor and virus infection therapy.In most delivery nanosystems,small molecules,photosensitizers,antigens,or other cargos are distributed in nanocarriers to prolong the cycle half-life,improve specific targeting,and reduce toxicity simultaneously.From the clinical translation perspective,liposomes,as FDA-approved carriers,are the most common and well-studied nanosystems.Polymers are relatively more emerging but also attractive due to their predominant physical and chemical properties,such as water solubility,biocompatibility,and storage stability.This thesis is to develop a novel delivery nanosystem based on poly(styrene-maleic anhydride)nanoparticles(PSMA NPs).Poly(styrene-maleic anhydride)has been applied in the clinic,but much uncertainty still needs to be explored.For instance,only a few systematic studies have investigated the correlation between different modification methods and biological activities when delivering the same molecule.Additionally,more attention should be paid to developing PSMA as a protein vaccine carrier in immunotherapy.Therefore,this study is to provide a systematic framework based on PSMA nanocarriers.It will attempt to carry out the novel structural design through regulations of physical and chemical properties while delivering multiple "goods"(photosensitizers,antigens,target ligands,etc.)to target cells or organs in specific treatment.The first part is to design nano photosensitizers for tumor-targeted imaging and phototherapy using the poly(styrene-maleic anhydride)nanosystem.Compared with the physical encapsulation reported in the past,indocyanine green(ICG),a NIR-Ⅱ fluorescent molecule,is covalently modified on the surface of poly(styrene-maleic anhydride)nanoparticles to optimize its performance in light absorption,aqueous stability,fluorescence imaging,and other aspects.Meanwhile,9-amino-sialic acid(9-SA)induced as a targeting ligand could further promote its cellular uptake,tumor-targeting specificity,and permeability.Finally,the covalently modified PSMA-ICG-9-SA NPs showed strong specificity,sustained fluorescence intensity,and eliminated large tumors(300 m3)in the mice tumor model.Therefore,this part provides a nanoengineering method for controlling fluorophore aggregation behavior and microenvironment to optimize nano photosensitizers through simple,economic,and clinical translation strategies.Moreover,the poly(styrene-maleic anhydride)nanosystem is designed as a anti-tumor vaccine platform targeting lymph nodes to induce strong humoral and cellular immunity simultaneously.Until recently,no previous study has investigated the application of poly(styrene-maleic anhydride)nanoparticles as protein vaccine nanoplatforms.So this part is the first attempt to utilize poly(styrene-maleic anhydride)nanoparticles as anti-tumor vaccine carriers to realize the activation of the MHC Ⅰ/Ⅱ pathway.Initially,we designed the first generation of the PSMA NPs vaccine that covalently linked the tumor model antigen ovalbumin(OVA).The formation of high-density antigens on the polymer surface promoted their interaction with antigen-presenting cells.Next,the second-generation water-soluble hPSMA NPs vaccine achieved higher stability,safety,and targeting ability through optimization in physical properties while inducing more effective tumor inhibition and higher antibody titers induction.In response to COVID-19 infection,the above-developed PSMA platform has been used to deliver novel coronavirus(SARS-CoV-2)protein antigen,including the receptor-binding domain(RBD)of the SARS-CoV-2 spike protein and nucleocapsid(N)protein.This part study provides an exciting opportunity to broaden the wide versatility and effective utilization of poly(styrene-maleic anhydride)nanosystems,further showing their clinical transformation possibility.Overall,this thesis focuses on a polymer nanocarrier,poly(styrene-maleic anhydride),which has excellent potential for clinical translation.The PSMA-based nanosystem is constructed in photothermal therapy and immunotherapy through new structural modification and design optimization.Notably,the PSMA nanovaccine preparation is the first successful attempt in current reports.This work can contribute to the clinical translation of PSMA-based nanocarriers further.