The Studies Of Nanomedicines Targeted To Tumor Vessels And Microenvironment

Cancer is one of the leading causes of abnormal death in the world,and the range it influenced is becoming more and more widespread.Therefore,the cure of cancer is an urgent problem to be solved.It has been shown that various therapeutic approaches could be associated with satisfactory results in this field in recent years.Tumor targeted therapy is a commonly used treatment strategy among them.The main tumor targeting strategies are passive targeting and active targeting.They had achieved a certain tumor suppressive effect,but still unable to cure cancers.More efficient tumor targeting strategies should be designed to achieve a better cancer therapeutic effect.Recently,the concept of tumor targeting has been further improved.Researchers showed more interests in targeting to tumor vessels or micro-environment,rather than tumor cells or organelles.For example,it has been widely accepted that angiogenesis plays a central role in driving tumor outgrowth and distant metastasis,as they provide oxygen and nutrients required for the progression of cancer and clear CO2 and metabolites.Accordingly,selective destruction of tumor vessels can act as a tumor suppressor effect;The variation in tumor microenvironment pH as low as 0.1 units can disrupt the ATP synthesis and some enzyme function in tumor tissues,inhibiting the proliferation,migration,invasion and metastasis of tumor cells.Therefore,selective regulation of microenvironment can also obtain the effect of tumor suppressor.Two kinds of tumor targeting treatment strategies were designed in this work.One is an enhanced radiotherapy using functionalized radiosensitizers based on tumor vessel targeting strategy.The other is a simultaneous in situ response-action strategy based on tumor microenvironment.The details are as follows:(1)AIRA NPs were designed as anti-RhoJ antibody,a tumor vessel targeting agent,modified Au@I nanoparticles.Au@I NPs,as radiosensitizers,could provide a superior radio enhanced effect,ranther than gold or clinical iodine alone.It can heighten the energy distribution in the surrounding tissue upon irradiation,which selectively damages the tumor tissue with a low dose of irradiation,and minimize the side effect to normal tissue.After functionalized with anti-RhoJ antibody,pre-existed deep tumor vasculature and peri-tumoral vessels can be selectively eliminated upon X-ray irradiation,which actively inhibits the tumor blood supply and induces the apoptosis of tumor cells in long lasting manner.This treatment also inhibits the metastasis of the tumor,and tumor vascularization and tumor recurrence did not observed after treatment.Also,as Au@I NPs possess CT enhancement,AIRA NPs were CT-guided tumor vessel-targeting radiosensitizers.(2)ACE-NPs were designed as targeted therapeutic strategy,using an acetazolamide encapsulating pH-responsive nanoparticles.The pH-responsive behavior was achieved by introducing hydrazone bond between PCL and PEG,and then nanoparticles were fromed by self-assembly.After their accumulation in the tumor tissue through the EPR effect,ACE-NPs will be degraded in the tumor faintly acid microenvironment,and the acetazolamide released from ACE-NPs may block the CA IX pathway,leading to the shutdown of transportation of extracellular HCO-3 to cytoplasmic matrix.Intracellular pH regulation of tumor cells,which survives them from hypoxia,will be inhibited.And then tumor cells would be killed,leading a tumor suppression effect.(3)ACE&PTX NPs was designed for the synergistic treatment of ACE-NPs and chemotherapy,basing on the improvement tumor faintly acid microenvironment by ACE-NPs.As the acidic environment plays a role in the resistance of tumor cells to drugs,the ability of ACE-NPs to improve tumor faintly acid microenvironment can enhance the efficiency of paclitaxel.More efficient tumor suppression effect was achieved through the synergistic treatment.