Preparation and Pharmacodynamic Study of Dihydroartemisinin/Cetylamine Coupled Prodrug Self-Assem-bed Nanoparticles
OBJECTIVE To design and release dihydroartemisinic(DHA)prodrug with long circulation ability in vivo by the stimulation of tumor cell microenvironment and improve drug accumulation in tumor site.METHODS DHA was covalently bonded to cetylamine(C16)carriers via disulfide(-SS-)and carbon-carbon bonds(-CC-)to synthesize two DHA/C16 coupled prodrugs of DHA-SS-C16 and DHA-CC-C16,which were formulated as self-assembled nanoparticles(DHA-SS-C16 NPs and DHA-CC-C16 NPs)by nanoprecipitation method.In vitro cellular studies were performed to assess the NPs'capacity in inhibiting the proliferation of 4T1 cells.Additionally,the pharmacokinetic behaviors in rats and the anti-tumor activity in 4T1 tumor bearing mice of NPs were also stud-ied.RESULTS DHA-SS-C16 and DHA-CC-C16 were successfully synthesized.The particle size and Zeta potential of DHA-SS-C16 and DHA-CC-C16 NPs were(115.7±3.0)and(106.6±1.0)nm,(-34.5±0.4)and(-21.3±0.5)mV,respectively.The average encapsulation efficiency and drug loading capacity of the two DHA/C16 coupled prodrugs were greater than 95％and 79％respectively,demonstrating good stability.NPs could inhibit the proliferation of 4T1 cells and reduce their migration ability.The phar-macokinetic studies showed that NPs prolonged the average retention time of DHA and enhanced the AUC of DHA to certain extent.The anti-tumor effect of DHA-SS-C16 NPs was better than that of DHA solution and DHA-CC-C16 NPs.CONCLUSION The self-as-sembled nano-drug delivery system designed in this paper,which utilizes disulfide bonds as connecting arm for DHA/C16-coupled prodrug,is capable of prolonging the retention time of drugs in the body,enhancing the accumulation of drugs at the tumor site,achieving responsive drug release in the tumor microenvironment,and improving anti-tumor effect.Furthermore,it also enhances the quality of life of mice.In conclusion,the nano-drug delivery system presents a promising long-acting and intelligent approach in drug delivery.
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