Design Paclitaxel/Sunitinib Co-delivery Polymer Micelles To Promote Antitumor Response For Triple-negative Breast Cancer

Triple-negative breast cancer(TNBC)has the characteristics of strong invasiveness,easy metastasis and poor clinical prognosis,so it is the most difficult to cure subtype of breast cancer in clinical treatment.Chemotherapy and surgery are still the main treatments for advanced TNBC.However,due to the multiple drug resistance of TNBC,complex tumor microenvironment(TME)and high metastasis rate,the existing treatment methods are difficult to produce effective inhibitory effect.In recent years,with the rapid development of immunotherapy,based on immunogenic cell death(ICD)induced by chemotherapeutic drugs can activate the immune system to achieve a better therapeutic effect.The combination of chemotherapeutic drugs and other drugs can enhance immune performance.However,the current chemical immunotherapy is limited by the different physical and chemical properties of combined therapy drugs,low administration efficiency and other factors.Therefore,it is still an arduous challenge to establish a combined delivery platform of combined chemotherapy and immunotherapy to improve the therapeutic effect of TNBC.As a co-delivery system,polymer micelles have the ability to load one or more drugs,and can control drug release,less side effects and biodegradability.in this paper,a Paclitaxel-Sunitinib polymer micelle co-delivery system was designed,and its anti-tumor effect in TNBC was evaluated.(1)The optimum ratio of Paclitaxel(PTX)to Sunitinib(SUN)was studied,and the amphiphilic polymer of poly(styrene-co-maleic anhydride)(SMA)was used as the carrier for drug delivery,and the two drugs were encapsulated in SMA in proportion.At the same time,the effects of SMA content,TEA content and preparation process on the physical and chemical properties such as particle size,Zeta potential and drug entrapment efficiency of Paclitaxel-Sunitinib co-delivery polymer micelles were investigated.The best prescription was selected to prepare nano-micelles for TNBC co-delivery system,and its stability was evaluated.The best combination ratio of PTX and SUN was 1:5(mol/mol).The average particle size of the prepared PTX-SUN co-deliveryed polymer micelles was 114.8 ± 2.96 nm,and the PDI was 0.118 ± 0.011.The Zeta potential was-42.73 ± 0.12 m V,and the stability was good.(2)A method for the determination of PTX in micelles by HPLC and SUN by UV-vis spectrophotometry was established,and the drug release behavior of drug-loaded micelles in vitro was studied.The results of drug release in vitro showed that SUN in PTX-SUN micelles could be released ahead of time,and PTX could be released later,with the characteristic of sequential release.(3)Using MDA-MB-231 cells as the research model,we systematically investigated the synergistic effect of the two drugs in drug-loaded micelles,and further discussed whether PTX combined with SUN could increase the induction of ICD in tumor cells.The experimental results show that the polymer micelle is safe and non-toxic,has good biocompatibility and meets the safety requirements of the drug loading system.PTX combined with SUN could effectively kill MDA-MB-231 cells,and its toxicity was not affected when loaded in micelles.Compared with free PTX,drug-loaded micelles can increase the exposure level of calcium reticulin on the surface of MDA-MB-231 cells and the extracellular release of HMGB1,promote the maturation of dendritic cells in vitro,thus effectively enhance the immunogenicity of MDA-MB-231 cells.