Synthesis And Drug-delivery Study Of Ph-responsive Rosin-based Tertiary Amine Derivatives

We designed and synthesized eight kinds of rosin-based tertiary amine derivatives with rosin as raw material,and explored their pH reponsiveness.We studied the self-assembly behavior,interface and mixtures' performance in the water system,which used in constructing the system of intelligent response targeted drug-delivery system.Delve into the relationship between the structure and performance of pH response functional rosin-based derivatives.The results are as follows:(1)Synthesis and characterization of rosin-based tertiary amine derivativesWe preparedfour tertiary amine by D-A addition,acyl chlorination and esterification reactions using rosin as raw material.Structures and purity of obtained products were characterized and analyzed.Finally,the molecular configurations were optimizedthrough quantum chemistry calculation.We obtainedrosin-based tertiary amine salts by acidification.(2)The interface performance and pH response performance research of rosin-based tertiary amine derivativesWe studied interfacial tension(?),critical micelle concentration(CMC),emulsifying performance(EP)and foam performance(FP).We studied the self-assembly behavious and pH-responsiveness.We found that maleic rosin-based tertiary amines have obvious pH-responsiveness.The self-assembly and pH-responsive mechanism of ertiary amine in aqueous solution were explored based on molecular packing density P values by quantum chemistry calculation.The pH-responsiveness property of maleic rosin-based tertiary amine is as follows:P is belower than 0.33 and molecular self-assembled into spherical micelles.P value increases to 0.33-0.5,molecular self-assembled into worm-like micelles.(3)The mixed performance of rosin-based tertiary amine derivativesWe mixed the MRDTA and MRETA with rosin-based phosphate diester(DDPD).The two kinds of mixed systems both have synergy.Synergy effection was the most optimum one in ?1=0.7 and ?2=0.7.MRDTAS and MRETAS were mixed with soapnut saponin.MRDTAS and soapnut saponin mixed systems have synergy in ?3=0.3-0.6.Synergy effection was the most optimum one in a3=0.3.MRETAS and soapnut saponin all have synergy,and synergy was the most effective in ?4=0.3.We mixed the ARDTAS with sodium dodecyl benzene sulfonate(SDBS).ARDTAS and SDBS mixed systemes have synergy in ?5=0.5,0.6 and 0.7.Synergy was the most effective in ?5=0.5.ARETAS and soapnut saponin all have synergy,and synergy was the most effective in a6=0.6.(4)Cell toxicity and drug-delivery studyThe cell toxicity of tertiary amine and tertiary amine salts for Human colorectal cancer cells(Caco-2)and Human cervical cancer cell(Hela),loading and encapsulation rate for hydrochloric acid doxorubicin(DOX),and drug cumulative release in vitro werestudied.Cell survival rates were 71.96%,71.96%,66.44%and 72.21%after training Caco-2 cells 72 hours in low concentration(10 ?g/ml)of MRDTAS,MRETAS,ARDTAS and ARETAS aqueous solutions.While,the cell survival rate at same rosin concentration was 62.63%.Cell survival rates were 98.17%,95.46%,92.18%and 97.34%after training Hela cells 72 hours in low concentration(100 ?g/ml)of MRDTAS,MRETAS,ARDTAS and ARETAS aqueous solutions.White,the lecithin cell survival rate was 98.56%at the same concentration.We also studied the targeted release performance of tertiary amine derivatives for DOX.MRDTAS,MRETAS/DDPD and ARDTAS/SDBS mixed systems have obvious targeted effect for DOX.The cumulative release rates of MRDTAS,MRETAS/DDPD and ARDTAS/SDBS mixed systems were 98%,86%and 93%at 24 hours under the condition of simulating cancer cell environment(pH=5.0),respectively.Targeted release rate were 31%,22%and 31%,respectively.MRETAS,ARDTAS and MRDTAS/saponins mixed system had good controlled-release effect for DOX.