Design And Synthesis Of Acid-sensitive Polyketal For Drug Delivery

In recent years, multifunctional biodegradable polymers have attracted great interests. Their stimuli-responsive properties give the controlled-release characteristics when they were used as drug delivery carriers. Among them, acid-degradable polymers were mostly used in drug delivery due to the acid microenvironment of some diseases, such as solid tumor and some acute inflammatory.In this thesis, firstly we designed and synthesized a new nomomor2,2-diglycidyl propane with a ketal bond through the ketal exchange approach using 2,2-dimethoxypropane and glycidol as raw materials.Then, using this monomer as a starting material, two kinds of polyketals with multiple pendent hydroxyl groups were designed and synthesized through the thiol–epoxy“click” reaction with bis(2-mer captoethyl) ether and through the amine–epoxy“click” reaction with piperazine respectively. They are two different types of click chemistry.The results showed that amine–epoxy“click” reaction which is catalyst free under ambient conditions, was simpler than thiol–epoxy“click”reaction. To probe the feasibility of potential application of these polyketals in biocomjugation, we explored a postpolymerization modification of hydroxyl groups with phenylacetyl chloride. The conjugation was confirmed by 1H NMR, GPC and other methods. Finally,the acid degradation property of these two acid-sensitive polyketals was studied. The results showed that these two polyketals were completely degradable under acidic conditions. As a comparison, the degree ofdegradation of polyketals was very small under neutral conditions.In addition to the synthesis of these two linear polymers above-mentioned, we also designed and synthesized a resveratrol containing hyperbranched acid-sensitive polymeric drug through the ketal exchange approach using 2,2-dimethoxypropane and resveratrol as raw materials.Then we modified the polymer by Williamson reaction with mPEG-OTs. The results showed that the final amphiphilic hyperbranched polymer was synthesized successfully. Next, we did a self-assembly experiments of this amphiphilic copolymers poly(resveratrol-co-ketal)-b-mPEG in aqueous solution. The results showed that nanoparticles with 90-120 nm diameters were fabricated by DLS and SEM. Finally we explored the acid degradation property of this hyperbranched polyketal. The results showed tha the polymer degraded completely under acidic conditions, and relatively stable under neutral conditions.