Delivery Of Triptolide With Polymer Nanoparticles For The Treatment Of Hepatocellular Carcinoma

Hepatocellular carcinoma(HCC)is the most common type of primary liver cancer and one of the deadliest malignant tumors in the world.Due to the characteristics of hidden disease,difficult early diagnosis and rapid growth of cancer cells,most of the patients were diagnosed in the late stage.The mortality rate of liver cancer is the second leading cause of cancer-related death[1].The active ingredient of traditional Chinese medicine(AIFCM),is becoming an effective anticancer drug for the treatment of hepatocellular carcinoma(HCC).Recent studies have demonstrated their potential to inhibit HCC initiation,cell proliferation,angiogenesis and metastasis.Triptolide(TP)is an active ingredient from the Chinese herbal medicine Tripterygium wilfordii and is a natural product with a variety of biological activities.Previous studies have shown that TP inhibits the growth of many kinds of cancer cells and is expected to be used as an effective chemotherapeutic agent at low concentrations.However,because of poor solubility,high toxicity and no targeting,TP will cause serious side effects,thus its potential clinical application of TP is limited.The diversification of nano-carriers provides more possibilities for the entrapment of TP.Nano-carriers have unique properties,such as nanometer size,high surface volume ratio and favorable physical and chemical properties.They have the potential to regulate the pharmacokinetic and pharmacodynamic characteristics of drugs,enhancing their therapeutic efficacy.Loading the drug into the nano-carrier can increase the stability in vivo,prolong blood circulation time of the compound,and allow the drug release to be controlled.In this study,we designed a polymer nano-drug loading system of TP for the treatment of liver tumors.The polymer contained disulfide reductive sensitive groups,coating TP to form uniform nanospheres.With an average particle size of 186 ± 10nm and the PDI of 0.163.After entering the tumor microenvironment with high GSH,the polymer nanoparticles coating TP released the encapsulated TP by breaking the disulfide bond.The drug endocytosis experiment suggested that more TP nanoparticles were endocytosed by HCC cells over time.Cell experiments in vitro showed that TP nanoparticles and their free drugs had greater toxicity and lethality to liver cancer cells than cisplatin,doxorubicin and sorafinib.In order to further verify the efficacy and safety of TP nanoparticles in the treatment of tumor,we subcutaneously transplanted human HCC tissue(patient-derived xenografts,-PDX)into BALB/c nude mice to establish a PDX model of HCC in nude mice.In vivo experiments showed that TP nanoparticles were more extensively distributed in the tumor site,had a longer residence time,had a greater inhibitory effect on tumor,had less effect on other normal organs,and higher safety,suggesting more efficient and less toxic than free drugs.In this study,polymer nano-drug loading system was used to carry out effective loading of active components of traditional Chinese medicine,and liver cancer cells and liver cancer PDX animal model were used to evaluate nano-drugs in vivo and in vitro.Our results showed that the nano-drug delivery system constructed in this paper has better tumor therapeutic effect and higher safety than other conventional tumor drugs.