| The boronic acid group is able to reversibly covalently bond with 1,2 or 1,3dihydroxy compounds to form stable cyclic ester structures.Taking advantage of this feature,in this study,3-carboxyphenylboronic acid was grafted onto the natural polymer material chitosan to prepare a phenylboronated chitosan material with H2O2environmental targeting function,and puerarin（Pur）was used as a model drug.Oral nanoparticles（PBACS-TPP-Pur-NPs）were prepared by ion gelation to verify the reliability of targeting and the effect of improving bioavailability.The specific research is as follows:（1）Synthesis of phenylboronated chitosan（PBACS）.Using EDCI and NHS as catalysts,the optimized acylation reaction conditions of chitosan and 3-carboxyphenylboronic acid were investigated,and the structure was verified by NHS and infrared to prove the material is successful synthesized.It is 15.7%-23.5%of the material,which provides crucial excipients for the preparation of PBACS-TPP-Pur-NPS.（2）Preparation and formulation optimization of PBACS-TPP-Pur-NPsUsing the Box-Behnken effect surface method,particle size,PDI,potential,encapsulation efficiency,and drug loading were used as evaluation indicators to investigate the material ratio of PBACS,the concentration of PBACS and TPP,p H,stirring speed,stirring time and other factors.The effect of ion gelation on the preparation of PBACS-TPP-Pur-NPs was optimized,and the optimal formulation process obtained was that the concentration of modified chitosan was 1.70 mg/m L,the TPP concentration was 1.20 mg/m L,and the modified chitosan concentration was 1.70 mg/m L.The sugar p H was 5.15,and the stirring speed was 380.00 r/min.The experimental results were verified to be consistent with the predicted values（P>0.05）,indicating that the preparation method was reliable.（3）Characterization of PBACS-TPP-Pur-NPs.The prepared nanoparticle suspension is clear and transparent,with obvious opalescence and Tyndall effects,and good stability.Infrared results showed that the characteristic peaks of Pur at 1630,1 445,1260,and 891 cm-1 were obvious after the physical process of Pur,PBACS and TPP,and the position did not shift and the intensity did not change significantly.The characteristics of puerarin in PBACS-TPP-Pur-NPs The peaks 1630,1 445,1260,and 891 cm-1 all shifted and weakened.The experimental results of simulated PBS and PBS+1%H2O2 in vitro showed that the cumulative release rate of Pur in PBS and PBS+1%H2O2 medium for 3h reached 99%,and the cumulative release rate of NPs in PBS+1%H2O2 medium for 12 hours reached 90%.After 12h in PBS medium,the cumulative release rate reached 80%,and then became stable.The H2O2-sensitive properties of the nanoparticles were shown.After fitting the equation of the PBACS-TPP-Pur-NPs to the Higuchi model,there was no burst release phenomenon during the release process,indicating that the PBACS-TPP-Pur-NPs were released in vitro.good.（4）Pharmacokinetic study of PBACS-TPP-Pur-NPsLC-MS/MS method for the detection of rat plasma samples with good reproducibility,high sensitivity and good specificity was established.Taking SD rats as the animal model,the pharmacokinetics of PBACS-TPP-Pur-NPS after oral administration was evaluated by gavage,and then compared with the control group the same dose of orally administered to mice after Pur pharmacokinetics were compared.The results of the study showed that the AUC0-24,AUC0-∞,Tmax,and Cmax of PBACS-TPP-Pur-NPS were 2.41,2.67,1.33,and 2.03 times higher than those of Pur,respectively.The relative bioavailability increased to 254.94%.It shows that the prepared nanoparticles can improve the absorption rate and absorption degree of Pur in vivo,obviously improve the bioavailability of Pur,and delay the release of Pur. |
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