Research On The Preparation Of Polyoxazoline-based Nanocarriers And Its Application In Tumor Therapy

Cancer is one of the most common causes of death in the world.Traditional chemotherapy and immunotherapy are still the best way to treat many cancers.However,traditional chemotherapeutic drugs and small-molecule antigens in immunotherapy have their disadvantages such as poor selectivity and low bioavailability in vivo treatment.Numerous studies have demonstrated that some effective improvements of selectivity,bioavailability,and tumor-suppressive effects could be achieved via the usage of nanocarriers to encapsulate small-molecule drugs or antigens.Based on the special chemical structure of hydrophobic small molecules,our research focused on the design of an efficient and versatile carrier an efficient and universal carrier for the delivery of small molecule drugs or antigens.The nano-formulations were used to evaluate the therapeutic effect of corresponding tumors,hoping to overcome the related problems in tumor treatment.The main contents and conclusions of this dissertation are summarized below:(1)Based on Poly(2-oxazoline)(POx),we designed and synthesized a series of amphiphilic POx copolymers containing different pendant groups,by using the interaction between different pendant groups and drugs to improve the loading efficiency of hydrophobic drugs on nanocarriers.The results showed that electrostatic interaction could effectively enhance the drug loading capacity of nanocarriers,while π-π interaction could only improve the drug-carrying capacity with high aromatic carbon content.In addition,none of the four functionalized POx nanocarriers showed obvious cytotoxicity and hemolysis in biocompatibility test.The results of placement stability experiments showed that most of the drug-loaded nano-micelles could maintain stable nano-micelle morphology after being placed at room temperature for a week.In summary,the experimental results showed that by modifying the POx nanocarriers with relative functional groups,all drugs we selected could be efficiently loaded,and the drug-loaded nano-micelles exhibited excellent stability at room temperature.It provided a new option for the subsequent development of nano-drugs.(2)The experimental results of the previous system proved that the POx nanocarrier with poly(2-butyl-2-oxazoline)as the hydrophobic chain was a preferred carrier for paclitaxel(PTX).However,the circulation time of PTX was undesired,which could not effectively improve the bioavailability of PTX in vivo.Considering this defect,we synthesized a pair of base-complementary core-crosslinked amphiphilic POx copolymers for loading PTX.The drug-loaded micelles with crosslinked structure were characterized by higher stability,smaller micelle size and higher PTX loading capacity.The in vivo biodistribution experiments in tumor-bearing mice demonstrated that the tumor accumulation of nuclear cross-linked micelles was 8.9 times that of free PTX.In tumor inhibition experiments,nuclear cross-linked drug-loaded micelles had the most significant inhibitory effect on two breast cancer tumors.The inhibition rates were higher than 80%.To sum up,the experimental results showed that the core-crosslinked POx copolymers could efficiently encapsulate PTX,and inhibit the growth of tumors,which provided a theoretical basis for the application of POx as medical nano drug carrier in clinical trials.(3)Therapeutic tumor vaccines could be used as a new type of tumor immunotherapy to provide an ideal choice for tumors that could not be cured by traditional treatment regimens.However,most of the antigens and adjuvants are small molecules,which could not be smoothly transported to the lymph nodes to induce an adaptive immune response.In response to this problem,we synthesized a series of POx nano-vaccine carriers containing tertiary amine groups as side groups,which were used to simultaneously carry OVA antigen peptides and adjuvant R848.This series of POx carriers.The results of in vivo experiments showed that the nanovaccine with tertiary amine modified POx as carrier could be efficiently enriched in lymph nodes,and induced the activation of DC cells and antigen cross-presenting capacity.In the tumor inhibition experiment of B16-OVA tumor-bearing mice,the nanovaccine with high piperidine-modified POx showed the greatest inhibitory effect on the tumor,and 50% of the mice in this treatment group were completely cured.In summary,the experimental results demonstrate that our synthesized tertiary amine-modified POx could simultaneously encapsulate OVA antigen peptide and adjuvant R848 and achieve simultaneous delivery of antigen and adjuvant.The effective inhibition of B16-OVA with the POx-based nanovaccine demonstrated a potential application of POx as a nanovaccine carrier in the medical field.