Construction And Activity Evaluation Of SN38-hydrogel Drug Delivery System

Colorectal cancer（CRC）is a malignant tumor in which cells in the colon or rectum divide or grow abnormally.The camptothecin drug 7-ethyl-10-hydroxycamptothecin（SN38）is effective in the treatment of colorectal cancer,but its application is limited due to its poor water solubility,low bioavailability and serious toxic side effects.Therefore,it is necessary to develop new drug delivery systems to fully exploit the therapeutic potential of SN38.Guanosine supramolecular hydrogels derived from natural products can deliver SN38 for the treatment of colorectal cancer due to their injectability,self-healing and biocompatibility.In this paper,a supramolecular hydrogel drug-loading system was prepared by simply mixing guanosine,SN38 and KOH in a ratio of 1:1:1 which was used to deliver SN38 and named[G-BSN38]₄K⁺.Firstly,¹H NMR,¹³C NMR and HRMS were used to verify the successful synthesis of BSN38.After the preliminary exploration and synthesis of[G-BSN38]₄K⁺hydrogel,the gel formation conditions were optimized and the optimal gel-forming were determined.The existence of hydrogel dynamic borate bond was proved by ¹H NMR,¹¹B NMR and FTIR.The chiral properties of[G-BSN38]₄K⁺hydrogel was proved by CD,TEM and AFM electron microscopy techniques demonstrated the microscopic morphological characteristics of the hydrogel nanofibers.The test results of rheological experiments showed that the hydrogels are self-healing and injectable.In vitro drug release studies showed that the drug release rate of hydrogel was significantly accelerated in the tumor microenvironment with low p H and high ROS,indicating that the hydrogel is responsive to p H and ROS stimulation and could achieve targeted delivery of the drug SN38.The anti-tumor activity of the hydrogel in vitro and in vivo was further evaluated.In the in vitro cytotoxicity experiment,human lung cancer cell line A549 and mouse colon cancer cell line CT-26 were selected for investigation,and the anti-cancer activity of the drug-loaded hydrogel was evaluated by measuring the IC₅₀value.In the A549 cell line,the[G-BSN38]₄K⁺hydrogel showed better anticancer effect than the free drug SN38.In the CT-26 cell line,the hydrogel showed comparable anticancer activity to the free drug.The non-loaded hydrogel material itself did not show obvious toxic and side effects.In the evaluation of anti-tumor activity in vivo,the CT-26 mouse tumor model was first established,and then Irinotecan（CPT-11）was used as a positive control for animal experiments.The results show that the mice in the hydrogel group have significantly reduced diarrhea and better tumor inhibition effect than CPT-11 group.The research of this work provides the possibility for clinical use of SN38 in the treatment of colorectal cancer to reduce the toxic and side effects.