Preparation Of Tumor Vasculature Microenvironment Regulating Nanodrugs And Their Anti-tumor Effects

Malignant tumors are one of the significant morbidities that seriously threatens the safety of people's lives and impose a substantial economic and social burden worldwide.Nearly ten million deaths occur due to malignant every year.Malignancies possess the characteristics of rapid proliferation and strong heterogeneity.The tumor microenvironment varies greatly between different tumor types and stages.Therefore,no effective therapeutic approach has been reported to cure the tumors.The current strategies for the treatment of cancer include chemotherapy,radiation,surgery,immunotherapy and tumor vascular targeting therapy and so on.Among them,tumor vascular targeting therapy is highly favored by clinicians and researchers because of its fast onset,strong universality,and not easy to induce drug resistance.A variety of drugs for tumor vascular targeting therapy have been approved clinically,including tumor angiogenesis inhibitor sorafenib,lenvatinib,bevacizumab and tumor vascular targeted embolization with microspheres gels.They have achieved remarkable therapeutic effects in malignancies with rich blood supply such as liver cancer and lung cancer,and greatly prolonged the survival time of patients.Although the tumor vascular targeted therapy strategies can effectively block the blood supply of tumor tissues,causing large-scale tumor necrosis,but the ability to kill cells at tumor edge that are independent of the tumor vascular blood supply is limited.Moreover,the ischemic-hypoxic microenvironment after tumor vascular targeted therapy also leads to strong tumor angiogenesis.Besides,the clinical application of tumor vascular targeted therapies was greatly limited due to the high toxicity of tumor vascular targeted drugs and the high technical difficulty of clinical embolization therapy.In this paper,with an eye to the above limitations of tumor vascular targeted therapy,three tumor vascular targeted drugs were designed and synthesized to improve the efficacy,tolerance and universality of tumor vascular targeted therapy,providing a theoretical basis for the clinical translation of tumor vascular targeted therapy.In the field of tumor vascular embolization,an intravenously injectable nucleic acid aptamer(AS1411)-truncated tissue factor(t TF)fusion protein(t TF-AS1411)was designed and synthesized.The AS1411 nucleic acid aptamer can not only specifically recognize the nucleolin protein on the surface of tumor vascular endothelial cells,but also own a good killing effect on the residual tumor cells and tumor vascular endothelial cells.Truncated tissue factor protein(t TF),as the extracellular segment of tissue factor,does not have coagulation activity itself due to the lack of structure integrity,but under the guidance of AS1411 nucleic acid aptamer,it can restore its coagulation activity on contacting the target cell membrane,and then induce a rapid coagulation response.To conclude this work,we synthesized a nucleic acid-protein complex(t TF-AS1411)that can be injected systemically with active tumor targeting ability.Besides,t TF-AS1411 effectively combines tumor vascular embolization therapy with chemotherapy to rapidly kill tumor tissues while inhibiting tumor recurrence.Not only that,as a tumor vascular embolization agent that can be administered systemically,it is more universal,eliminating the need for imaging technology-guided interventional procedures,greatly reducing the risk of surgery and anesthesia for patients and radiation exposure for doctors.The experimental results showed that the t TF-AS1411 fusion protein can efficiently target tumor tissue and cause vascular embolism in tumor tissue,block the blood supply,and induce tumor apoptosis and necrosis.Compared with traditional tumor vascular embolization agents,t TF-AS1411 can also simultaneously kill residual tumor cells and tumor vascular endothelial cells,leading to stronger anti-tumor effect and longer survival time of mice.In the field of tumor blood vessel disruption therapy,a platelet membrane biomimetic smart nanomedicine was designed and synthesized.We use the mesoporous silicon nanocarrier as the core,which carries the tumor blood vessel disrupting agent combretastatin A4(CA4)and the angiogenic inhibitor apatinib,and finally coats the platelet membrane on the surface to form the final nanomedicine MSN@PM-C-A.Benefiting from the EPR effect of nanodrugs and the tumor-targeting and wound-targeting capabilities of platelet membranes,MSN@PM-C-A nanodrugs can achieve specific enrichment in tumor tissue,and then selectively destroy tumor blood vessels.In addition,after tumor blood vessels were destroyed,MSN@PM-C-A nanomedicine can be further targeted to the damaged tumor tissues with the wound targeting ability of platelet membrane,where they release the blood vessel destroying drug CA4 and trigger further destruction of tumor blood vessels.Then,the targeting ability of MSN@PM-C-A nanomedicines was further enhanced,thus realizing the cascade amplification and enrichment of nanomedicines in tumor tissue,and greatly improving the efficacy of tumor vascular destruction therapy.To sum up this topic,we synthesized a nanodrug that can selectively destroy tumor blood vessels,and at the same time release tumor angiogenesis inhibitory drugs in the tumor in situ to inhibit tumor angiogenesis after tumor blood vessel destruction,and the nanodrug produced good therapeutic effect in a mouse liver cancer model.The experiments showed that the MSN@PM-C-A nanomedicine can induce tumor tissue necrosis and apoptosis while effectively inhibiting tumor tissue angiogenesis,which provides a novel theoretical basis for the clinical treatment of hepatocellular carcinoma and other blood-rich tumors.In the field of tumor angiogenesis inhibition therapy,to improve the efficacy of existing clinical tumor angiogenesis inhibiting drugs and reduce their systemic side effects,we combined tumor angiogenesis inhibition therapy with immunotherapy for the prevention of postoperative recurrence of liver cancer.The three-year postoperative recurrence rate of liver cancer exceeds 50%,and the efficacy of anti-angiogenic drugs alone is very limited after surgery.Besides,patients with postoperative recurrence of liver cancer are often accompanied by severe immune suppression in the tumor microenvironment.Therefore,to effectively inhibit the postoperative recurrence of liver cancer,we used mesoporous silicon nanoparticles(MSN)to efficiently load the clinical first-line anti-angiogenics drug sorafenib,then coated the platelet membrane on the surface of MSN,and finally covalently linked the immune checkpoint inhibitor anti-PDL on its surface to form the final a-PM-S-MSNP nanodrug.Taking advantage of the wound and tumor targeting capabilities of platelet membranes,a-PM-S-MSNP nanomedicine can be specifically enriched in the postoperative surgical margin of tumors,inhibiting the angiogenesis induced by residual tumor tissue and ameliorating the immunosuppressive microenvironment.Besides,the a-PM-S-MSNP nanodrug can reduce the systemic toxicity of immunotherapy and anti-angiogenic drugs while exerting strong anti-tumor efficacy,which possesses certain potential for clinical application.To summarize this topic,we synthesized a nanodrug that can actively target tumor postoperative margins and implement tumor-site-directed release of immune checkpoint inhibitors and anti-angiogenic agents.The a-PM-S-MSNP nanodrug can significantly improve the tumor killing ability of the immune system,remove residual tumor cells after surgery,and at the same time inhibit the formation of tumor angiogenesis,thereby inhibiting the postoperative recurrence of early hepatocellular carcinoma.The experimental results indicated that the a-PM-S-MSNP nanodrug can effectively inhibit the angiogenesis in residual tumor tissues,alleviate the immunosuppressive microenvironment and enhance the killing effect by the immune system.In the orthotopic hepatocellular carcinoma recurrence model,the a-PM-S-MSNP nanodrug significantly inhibited the postoperative recurrence of hepatocellular carcinoma and greatly prolonged the survival of mice.This work provided experimental evidence and theoretical basis for clinical postoperative treatment of hepatocellular carcinoma.