| Cancer is a huge global burden in the worldwide,the tendency of incidence and modality is increasing.In 2020,there were 19.29 million new cases of cancer and 9.96 million deaths in the whole world.Lung cancer has the highest modality rate among the cancers,and the 5-year survival rate is only 10%-20%.Although numerous innovative therapies have emerged such as immunotherapy,targeted therapies,and et.al,chemotherapy remains the cornerstone of entire treatment form first-line to the end of therapy.Most chemotherapeutic drugs can only be administered with intravenous route because of their chemical characteristics,including low water solubility,unstable in gastrointestinal tract,and poor intestinal permeability.Traditional chemotherapeutic route always has poor patient compliance,in addition,some elderly patients with blocked veins cannot respond to treatment by intravenous injection.Oral chemotherapy can overcome the toxicity,drug-resistance,poor compliance,et.al,caused by intravenous injection,therefore the development of oral chemotherapy is of great value.The development of oral chemotherapy is confronted with great challenge,which including:1)improving water solubility of drugs;2)improving the gastrointestinal stability of drugs;3)enhancing the ability of overcoming multi-physicochemical barriers.Therefore,the aim of this study is to design oral chemotherapeutic delivery systems for enhancing oral bioavailability of chemotherapeutic drugs,and provide new strategies for the development and clinical application of chemotherapy.In order to overcome mucus and intestinal barriers after oral administration,and provide strategies as well as theoretical support for the research of oral chemotherapy,two kinds of oral nano-system was constructed based on bile acids-modification.1)For the intestinal epithelium barrier,bile acids modification was employed.Herein,bile acids are endogenous substance secreted by human body,which can recognize ASBT expressed in enterocytes and further transport into circulation.In order to further enhance trans-epithelial ability,quercetin,an intestinal P-gp inhibitor,was introduced into our delivery system;2)For mucus layer barrier,the two parts of this study discussed the biological functions and mechanisms of mucosal adhesive materials and mucus penetrating materials,respectively.This study chose the most typical anti-cancer drugs paclitaxel(PTX)as model drugs.PTX is a kind of taxanes,at present,most PTX formulations in market are administrated with intravenous route.The water solubility and intestinal permeability of PTX is extremely poor,therefore,oral bioavailability of PTX is lower than 1%.There is only one oral PTX formulations been approved for market use,and is only restricted to be approved in Korea,and listed of oral PTX formulations are in the clinical stage.The clinical efficacy and safety data showed that oral PTX delivery systems have great potential in clinical application.Oral route can enhance patients’ compliance,therefore,design of oral PTX delivery systems have great application value.This study is consisted of two parts,PTX was used as model drugs.In project 1,oral nano-micelles combined mucus penetration and intestinal active targeting function was prepared.In project 2,oral complex nanoparticles combined mucosal adhesive,intestinal active targeting,and intestinal P-gp inhibitory function was synthesized.The efficiency of intestinal endocytosis and trans-epithelium behavior was evaluated on cell and animal levels.In vivo results in project 1 showed that,oral bioavailability of PTX was increased 6.4-fold compared with oral Taxol,and the efficacy was similar to that of Taxol with intravenous route in LL2-mice model.In vivo results in project 2 showed that,oral bioavailability of PTX was increased 18.5-fold compared with oral Taxol,and the efficacy was superior to that of Taxol with intravenous route.In the meanwhile,in vivo safety was improved compared with intravenous injection. |
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