| Objective: Oral administration is so far the most widely used mode of administration. But the effects of drugs through gastrointestinal tract in this complex environment will be affected by intestinal epithelial cells and intestinal enzymes. Studies have demonstrated that intestinal epithelial cell membrane P-glycoprotein(P-gp) on oral drug across biological membrane transporters and drug use can have a significant impact. P-gp can energy dependence of the absorption of the drug to pump into the intestinal lumen, which is main factor to restrict the absorption of P-gp substrate drugs, and to be oral drug absorption of important barriers. Our previous study has confirmed that pluronic block copolymer has a certain degree of P-gp inhibition, and found that SWCNTs may also have effect of P-gp inhibition. For this reason, We envision combined use of the SWCNTs having P-gp inhibition and Pluronic, and use this new nanocomposite build a new oral drug self-assembled systems, which can not only solve the problem of water-dispersible, but can also effectively improve the P-gp substrates medication orally bioavailable availability in the use of double inhibition of P-gp. The above assumption Provides a new idea for the study of SWCNTs oral drug delivery system.Methods:(1) Preparation of nanocomposites Pluronic/SWCNTs In order to determine the optimal dispersion conditions SWCNTs, we put the appearance, the maximum UV Vis absorption, particle size as the evaluation index and investigated the dispersion method and Pluronic dispersion agent type, SWCNTs feeding amount, ultrasonic power and frequency factors of SWCNTs dispersion effect.(2) Toxicity of Pluronic/SWCNTs on Caco-2 cells MTT assay and LDH activity assays were investigated Pluronic/SWCNTs of Caco-2 cell toxicity.(3)Caco-2 cell model studying Pluronic/SWCNTs intestinal P-gp inhibition of drug pumps With the choice of Caco-2 cell model,P-gp substrates with rhodamine 123(R-123) as a fluorescentprobe drugs and P-gp inhibitors verapamil hydrochloride as a positive contro,to investigate effect of Pluronic/SWCNTs of R-123 cellular uptake.By HPLC for quantitative analysis of R-123 and SPSS software for statistical analysis of the results, We can research Pluronic/SWCNTs of P-gp inhibition of drug pumps.(4) Using rat single-pass intestinal perfusion further verificate Pluronic/SWCNTs of intestinal P-gp drug pump inhibition.Results:(1) Using ultrasonic dispersion method, 10mg/mlF127 and F68 as auxiliary materials and 260 W ultrasonic power, 40 times, we managed to spread SWCNTs.(2) The experimental results of MTT and LDH show that Pluronic/SWCNTs have no effect on the growth of Caco-2 cells n the range of experimental concentrations.(3) The caco-2 cell uptake experiments show that high concentrations of Pluronic/SWCNTs promoting cell uptake of a lower concentration of weak In the range of experimental concentrations; For F127/SWCNTs,SWCNTs play a leading role in promoting the role of cellular uptake with a concentration of5~10μg/mL and F127 play a leading role at concentrations above 50μg/mL; For F68/SWCNTs,SWCNTs play a leading role in promoting the role of cellular uptake and F68 promote cellular uptake less effective.(4) In situ intestinal perfusion experiments show that Pluronic/SWCNTs promote intestinal absorption significantly higher than Pluronic presence alone,Pluronic/SWCNTs promote intestinal absorption in a concentration-dependent manner and Pluronic/SWCNTs have the most significant effect of promoting intestinal absorption at a concentration of 50μg/mL.Conclusion: From the above results, different compositions Pluronic/SWCNTs can promote the absorption of transmembrane P-gp substrate R-123 to a certain extent. It should have a different degree of inhibition of P-gp. The building method of Pluronic/SWCNTs self-assembly system of oral drugs is scientific, simple, good repeatability, stability and biocompatibility,strong P-gp inhibition, can provide the basis for improving bioavailability of P-gp substrate drugs. |
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