Synthesis And Characterization Of PH-responsive Antitumor Polymer Prodrugs Bonded With Hypoxia Responsive Drug

Cancer’s disease incidence is increasing year by year.However,now,the main ways to treat tumors are surgical removal and radiotherapy and chemotherapy,which will cause great pain to the patient and high recurrence rate.This is because tumors grow to a certain extent to resulting in that the metabolic wastes far away from the blood vessels will be difficult to remove and eventually form an oxygen-deficient environment.When tumor cells are under hypoxic environment for a long time,tumor cells will transform hypoxic tumor cells.Hypoxic tumor cells possess several times resistant to radiation and chemotherapeutics than aerobic cells.Therefore,the treatment of hypoxic tumor cells is one of the focal point of current research.Tirapazamine is a new anti-tumor drug which has the characteristics of hypoxia sensitivity,and will not cause damage to normal human tissue cells.When Tirapazamine is under hypoxic environment,it can generate a free radical to damage cells.In this paper,the method of bonding Tirapazamine is used to improve the therapeutic effect on hypoxic tumor cells.In this paper,We use lactide containing norbornene group and m PEG₅₀₀₀ to carry out ring-opening polymerization to obtain the amphiphilic polymer backbone m PEG₅₀₀₀-b-PLA.Then,through“thiol-ene"click reaction,we use Click reaction ofβ-Mercaptoethylamine and m PEG₅₀₀₀-b-PLA to obtain the polymer m PEG₅₀₀₀-b-P（LA-g-S-NH₂）whose side groups is amino groups.Then use TPZ to react with p-formyl benzoic acid,and obtain TPZ molecules with aldehyde groups.The polymer m PEG₅₀₀₀-b-P（LA-g-S-NH₂）whose side groups is amino groups and the modified aldehyde-based Tirapazamine（TPZ-CHO）are subjected to Schiff base reaction,and finally obtain intelligent type of polymer bonding drug m PEG₅₀₀₀-b-P（LA-g-S-N=C-TPZ）.Under the environment of pH=7.4,the particle size of the polymer prodrug nanoparticles remain at 110nm within 24h,and the drug loading is11.34wt%.In vitro drug release experiments show that the polymer prodrug is pH sensitive and can release drugs quickly in a weakly acidic environment that mimics tumors.Combretastatin A4（CA4）is an excellent vascular occlusion agent,which can target the tumor blood vessels,cause irreversible damage to the tumor,and can aggravate the degree of hypoxia in the tumor environment.It can be used in combination treatment cancer with Tirapazamine.Use Combretastatin A4 to react with p-formyl benzoic acid to generate aldehyde-based Combretastatin A4（CA4-CHO）.Then use CA4-CHO and TPZ-CHO“one-pot”method to react with m PEG₅₀₀₀-b-P（LA-g-S-NH₂）with Schiff base,and finally obtain intelligent type of polymer bonding drug m PEG₅₀₀₀-b-P（LA-S-N=C-（g-TPZ-g-CA4））.Under the environment of pH=7.4,the particle size of the polymer prodrug nanoparticles is basically maintained at 120nm within 24h.Among them,the drug loading of TPZ is2.52wt%and the drug loading of CA4 is 11.58wt%.The in vitro drug release experiments show that the polymer prodrug has less drug release and great stability under the environment of pH=7.4.Under the environment of pH=5.6,both drugs will be released quickly.