Preparation And Characterization Of Antitumor Nanosystems Bonded With Hypoxic Responsive Drug

The morbidity and mortality of cancer is growing rapidly around the world,and cancer becomes the most important factor which hindering the improvement of life expectancy.During the process of tumor tissue enlargement,the early stage belongs to the avascular phase,which mainly relies on normal blood vessels for proliferation.In the later stage,cell metabolites cannot be removed and the inadequate supply of nutrients and oxygen.In addition,the microenvironment of the tumor away from the blood vessels will deteriorate and hypoxic environment will occur,causing some tumor cells turn into hypoxic tumor cells.Hypoxia can activate the expression of specific genes in tumor cells,produce various signal factors to facilitate the proliferation of tumor cells,and induce the tumor capillaries.Then tumor cells proliferate wildly again and form a vicious circle.The tumor cells which are close to the tumor vessels will enter the blood vessels for circulation.On the contrary,the hypoxic tumor cells are far away from the tumor vessels so the anti-tumor drugs contained in the blood cannot easily to eliminate these type of tumor cells and they are easier to evade the body's immune system,resulting in unsatisfactory effects of chemotherapy and radiotherapy.As a result,the tumor is common to metastasize and recur after treatment.Due to the fact that most of the chemotherapeutic drugs can induce tumor cells to express drug resistance genes in the process of proliferation and lack of cell targeting,so it is urgent to study a new drug for treating the hypoxic tumor cells.In this paper,polyethylene glycol monomethyl ether(mPEG₅₀₀₀,Mw:5000)was used as a hydrophilic chain of polymer prodrug carrier to initiate the ring-opening polymerization of the modified lactide monomer containing pendant norbornene groups.Then the amphiphilic polymer mPEG₅₀₀₀-b-P?LA-g-S-COOH?was obtained by the light click reaction to introduce carboxyl groups into the pendant norbornene groups.The reaction conditions of the thiol-ene click reaction were mild,the yield was high,and the by-products were few.It is convenient to introduce active groups into the main chain of the polymer prodrug.The hydroxylated tirapazamine?TPZ-OH?was bonded to the polymer by a condensation reaction to obtain the mPEG₅₀₀₀-b-P?LA-g-S-TPZ?.As a result,the average particle size of the prepared nanoparticles was 53.2 nm,PDI was 0.351 on average at 24 h.Moreover,the size of the nanoparticles remained within100 nm after 72 h,and the drug loading was 13.25%.In addition,based on the above experiments,tirapazamine and combretastatin A4were co-delivered by amphiphilic polymer mPEG₅₀₀₀-b-P?LA-g-S-COOH?to bond drug molecules so as to product the mPEG₅₀₀₀-b-P?LA-g-TPZ-g-CA4?.The result showed that the average particle size of the prepared nanoparticles was 82.5 nm,the PDI was 0.473 at 24 h,the drug loading of TPZ was 3.33%,and the CA4 was 16.01%.The two polymer prodrugs of mPEG₅₀₀₀-b-P?LA-g-S-TPZ?and mPEG₅₀₀₀-b-P?LA-g-TPZ-g-CA4?were formed in aqueous solution and controlled release in vitro at different pH values,enzyme and enzyme-free.The results showed that the two polymer prodrugs prepared in this study enjoyed better stability in the absence of enzymes,which is expected to prolong its blood circulation in the body and increase the accumulation of the drugs remained in tumor tissues for anti-tumor.