| Nano Drug Delivery System(NDDS)is the application of nanotechnology in the medical field and is widely used in the diagnosis and treatment of diseases.Atherosclerosis(AS),a chronic cardiovascular disease,is one of the leading cause of death.The use of NDDS for the treatment of chronic diseases showed good applications prospect.Rapamycin(RAPA)has an anti-atherosclerotic effect,however its clinical use is limited by its poor water solubility.Among different NDD systems,nanoparticles(NPs)may improve drug solubility as well as site delivery through EPR effect.In this study,two kinds of NDD systems were prepared for RAPA delivery.In one hand,polymeric NPs,based on amphiphilic PEG-PLGA(Polyethylene glycol-poly(lactic acid-co-glycolic acid))copolymer,were prepared using solvent displacement method.The particle size of RAPA loaded PEG-PLGA NPs was around 120 nm with an encapsulation efficiency of 81% and drug loading of 3.7%.The in vitro drug release has showed a sustained release of RAPA from NPs,and cumulative release of 65% after 6 days.The RAPA-loaded PEG-PLGA NPs had a significant inhibitory effect on the proliferation of Raw 264.7 macrophages and Jurkat T cell compared to free RAPA,and slightly inbibited the proliferation of HFF-1 cells.Pharmacokinetics study on BALB/c mice displayed higher bioavailability of RAPA in blood compared to free drug.In this study,RAPA-loaded PEGPLGA NPs were successfully prepared by a simple method and showed better pharmacological effects than free RAPA.However,the passive targeting through EPR effect might be a limitation for efficient site delivery of PEG-PLGA NPs.Therefore there is a necessity to design a new carrier with an active targeting propriety to achieve enhanced therapeutic effect.On the other hand,NDDS based on high molecular weight hyaluronic acid(HA),an active ligand for cell surface receptors related to AS.HA was primarily modified with adipic acid dihydrazide(ADH)to prepare HA-ADH derivative,which was reacted with retinal(ATR)to obtain HA-ATR polymer with pH-sensitive hydrazone bond and self-assembly ability.RAPA was loaded using sonication and dialysis methods.The experimental conditions in the preparation of HA-ATR NPs were optimized.The optimized NPs were characterized in terms of particle size,morphology,drug release and cytotoxicity.The particle size was about 450 nm with uniform spherical shape,the encapsulation efficiency was 40% and the drug loading was 12%.The in vitro release study conducted at different pH values has proven the pH sensitivity of HA-ATR NPs,the release rate of the NPs at pH 5.5 was higher than that at pH 6.5 and 7.4.In order to decrease the particle size of HA-ATR NPs,TPGS was used to enhance hydrophobic interaction between RAPA,ATR and vitamin E,allowing for more compact core formation.After optimization,HA-ATR-TPGS NPs size was decreased to 300 nm,and the encapsulation efficiency and drug loading were improved to 59% and 17%,respectively.The spherical appearance of the RAPA-loaded HA-ATR-TPGS NPs was observed by TEM and AFM.The CCK-8 assay showed that RAPA loaded HA-ATR NPs and RAPA-loaded HA-ATR-TPGS NPs both had a significant effect inhibitory effect on the proliferation of Raw 264.7 cells and slightly inbibited the proliferation of HFF-1 cells.In conclusion,the prepared NDDS in this study could achieve efficient encapsulation of RAPA,laying the foundation for further cell and animal experiment for atherosclerosis treatment. |
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