Construction Of ¹³¹I-FAP-loaded Dextran Microspheres And Preliminary Study Of Intervention Embolization Therapy For Rabbit VX2 Liver Tumor Model

Objective:Construction of one kind of embolism-visualized preparations named¹³¹I-Tyr-FAP-2286-DMs.To investigate the therapeutic effects of intervention embolization treatment with dextran microspheres（DMs）and transcatheter arterial radioembolization（TARE）with ¹³¹I-DMs or ¹³¹I-Tyr-FAP-2286-DMs on rabbit VX2liver tumor model.Method:The apparent morphology of DMs（20-70μm）screened by steel sieves was observed under light microscopy and the particle size distribution was determined.Tyr-FAP-2286-DMs was prepared by introducing tyrosine-linked fibroblast activation protein binding peptide analogs（Tyr-FAP-2286）at the hydroxyl end of DMs through esterification reaction.The drug loading rate was determined by high performance liquid chromatography（HPLC）.DMs and Tyr-FAP-2286-DMs were labeled with iodine-125(¹²⁵I)by the Iodogen method,and the cumulative release of ¹²⁵I was investigated.¹³¹I-DMs and ¹³¹I-Tyr-FAP-2286-DMs were prepared by Iodogen method for iodine-131(¹³¹I)labeled.Rabbit mesenchymal epidermoid squamous carcinoma（VX2）tumors were transplanted into the liver of thirty-six adult New Zealand rabbits to construct rabbit VX2 liver tumor models.¹⁸Fluorine-fluorodeoxyglucose(¹⁸F-FDG)positron emission computed tomography/computed tomography（PET/CT）imaging was conducted to select the enrolled models.Rabbit VX2 liver tumor models were randomly grouped,2 pieces per group,for intervention embolization with DMs and TARE treatment with¹³¹I-DMs and ¹³¹I-Tyr-FAP-2286-DMs,respectively.The embolization effect of¹³¹I-DMs or ¹³¹I-Tyr-FAP-2286-DMs and the distribution of ¹³¹I in vivo were assessed by single photon emission computed tomography/computed tomography（SPECT/CT）imaging at 0,12 and 24 h.The active degree of tumor metabolism in each group of rabbits was observed by ¹⁸F-FDG PET/CT imaging to assess the tumor activity and treatment effect.The liver tumor and tumor peripheral tissues were taken at 15 days after surgery for pathological study.Result:The DMs surface was bright and round.The DMs particle size ranged from 20-70μm and average particle size was 32.41±9.08μm,which was suitable for TARE treatment.Tyr-FAP-2286-DMs was successfully prepared by esterification synthesis.The encapsulation rate of Tyr-FAP-2286 was up to 55.52±7.60%,and the drug loading rate was 0.0278%.Construction of ¹³¹I-DMs and¹³¹I-Tyr-FAP-2286-DMs labeled by Iodogen method was successful.Rabbit VX2 liver tumor models were successfully constructed.SPECT/CT images showed good stability of ¹³¹I-DMs and ¹³¹I-Tyr-FAP-2286-DMs embolization in vivo and ¹³¹I uptake at the tumor site in liver.¹⁸F-FDG PET/CT imaging results showed a maximum rate of change in SUV_maxvalues of 53.62±10.29%between the day before treatment and 5days after ¹³¹I-Tyr-FAP-2286-DMs treatment.Pathological results showed extensive necrosis and fibrosis of tumor cells after ¹³¹I-Tyr-FAP-2286-DMs treatment.Conclusion:The particle size and good swelling properties of DMs conform to the requirements of embolization for TARE.The ¹³¹I-Tyr-FAP-2286-DMs constructed by the Iodogen method has good stability in vivo.¹³¹I-DMs and¹³¹I-Tyr-FAP-2286-DMs can be visualized by SPECT/CT imaging.The nucleotide distribution can be captured,which provide a reference for the prediction of the embolization effect and therapeutic effect.¹³¹I-Tyr-FAP-2286-DMs was superior to¹³¹I-DMs and DMs in the treatment of rabbit VX2 liver transplantation tumors by analyzing ¹⁸F-FDG PET/CT imaging and pathology.¹³¹I-Tyr-FAP-2286-DMs effectively reduced tumor activity and had a strong killing effect on tumor cells.This study optimized the drug delivery mode of DMs and provided a feasible option for functionalized TARE.