Rapid Preparation Of PH/temperature Dual-responsive Drug Delivery Nanoparticles And Its Performance Study

Polymeric drug carriers have emerged as one of the most promising and viable technology platforms for controlled drug delivery.However,single-response systems are not sensitive enough,and complex responsive drug delivery nanosystems usually face difficulties in design,cumbersome synthesis process,low drug delivery rate,and poor reproducibility.In this thesis,a series of pH/temperature dual-responsive drugdelivery nanosystems were designed to improve the drug release performance in one step,and the flash nanoprecipitation and flash nanocomplexation methods were used to complete the rapid and controllable preparation of drug-delivery nanosystems.The main findings are as follows.(1)A series of random copolymers of DMAEMA and NIPAM with different DMAEMA contents,PDMAEMA-co-PNIPAM,were synthesized using a free radical polymerization method.The successful synthesis of the polymers was demonstrated by NMR and IR characterization,and the LCST of the polymers was shown to increase with the content of PDMAEMA monomer by variable temperature UV.The polymer with 50% PDMAEMA content(whose LCST is 38.6℃,which is suitable for human body temperature)was selected for the rapid and controllable preparation of pH/temperature dual-responsive drug-loaded nanoparticles by Flash nano-precipitation,using the complexation system between the polymer and sodium phytate as the carrier,and the hydrophobic effect of the polymer as the driving force to encapsulate the hydrophobic drug β-carotene.The successful drug encapsulation was demonstrated by IR.The encapsulation rate was up to 76% and the drug loading rate was up to 24.7%.Dynamic light scattering data showed that the particle size could be tuned between 60-140 nm by changing the flow rate and drug concentration during preparation,and the morphology was further determined by TEM.In vitro release experiments showed that the release rate of this drug delivery system was significantly higher at pH 5.7 than that at pH 7.4,and the release rate at 37 ℃ was also significantly higher than that at 25 ℃.The drug release model was analyzed by release kinetic simulation,and the release behavior was found to be in accordance with the Weibull model,which indicated that the release process was in accordance with Fick’s law of diffusion,and the drug release process of this drug delivery system was driven by the drug concentration difference,and the drug diffused from the substrate body to the substrate surface to finally complete the drug release.(2)A dual pH/temperature sensitive drug loading nanosystem was prepared by using the Flash nanocomplexation method as a preparation platform,using the charge interaction between pH-sensitive sodium carboxymethylcellulose and the anticancer drug DOX for the first step of drug loading,and using the temperature-sensitive PDMAEMA-co-PNIPAM for the second step of drug loading.The smooth drug loading was demonstrated by infrared spectroscopy with a drug loading rate of 24.7% and an encapsulation rate of 77.6% for the drug.Dynamic light scattering data showed that the particle size could be tuned between84-220 nm by varying the conditions of flow rate and concentration during the two-step hedging process.The nanoparticle sizer data showed that the zeta potential increased from-26.14 mV to +5.38 mV with increasing polymer concentration during the assembly process.it was observed by TEM that the assembly results gradually became homogeneous with increasing polymer concentration,and a distinct core-shell structure could be seen.In vitro release experiments showed that the release rate at pH 5.7 was significantly higher than that at pH 7.4,and the release rate at 37℃ was also significantly higher than that at 25℃.The drug release rate at 37℃ pH 5.7 was 58.2% higher than that at 25℃ pH 7.4 within 48 h.The release rate of the drug at 37℃ pH 5.7 was significantly higher than that at 25℃ pH 7.4.The slow release model was also analyzed by release kinetic simulation,which showed that there was no dissolution of the matrix during the release process,and the drug was released by diffusion from the dissolved matrix to the surface of the matrix.(3)The random copolymer of acrylic acid with N-isopropylacrylamide,PNIPAM-co-PAA,was synthesized by free radical polymerization,and its successful synthesis was demonstrated by NMR hydrogen spectroscopy as well as IR spectroscopy.Its LCST was proved to be 38℃ using variable temperature UV.The drug-loaded nanoparticles DOX@PNIPAM-co-PAA were prepared by Flash nanocomplexation using the complexation ability between the polymer and DOX as a model drug,and furthermore,the drug-loaded nanoparticles with core-shell structure were prepared by second-step encapsulation using nano transient complexation using the ionic complexation ability between the polymer and chitosan,and the pH/temperature dual-responsive drug-loaded nanoparticles DOX@PNIPAM-co-PAA@CS with a high encapsulation rate of 67.4% and a drug loading rate of 13.5% were prepared.The dynamic light scattering data showed that the particle size could be regulated between 86-1500 nm by changing the flow rate and concentration conditions during the two-step hedging process.The dynamic light scattering data and TEM results together proved that the nanoparticles became more homogeneous in size after the second assembly step,and their PDI decreased from 0.213 to 0.0602,and the nanoparticle size measurement data showed that their In vitro release experiments showed that the release rate at pH 5.7 was significantly higher than that at pH 7.4,and the release rate at 37℃ was also significantly higher than that at 25℃,where the drug release rate at pH 5.7 at 37℃ was 48.8% higher than that at pH 7.4 at 25℃.48.8%.The drug release model was also analyzed by release kinetic simulation,which showed that there was no dissolution of the matrix during the release process,and the drug was released by diffusion from the dissolved matrix to the surface of the matrix.