Tumor-penetrating Peptide IRGD Enhances The Anti-tumor Efficacy Of Radiotherapy

Purpose:Accurate radiotherapy is widely used in the treatment of primary and metastatic tumors.With the innovation of radiotherapy technology and hardware,the local tumor control probability of radiotherapy has gradually increased.However,due to the complicated tumor microenvironment,it is still very meaningful to improve the effect of radiotherapy and maintain long-term anti-tumor efficacy.A tumor-penetrating peptide,iRGD could enhance the efficacy of anti-cancer drugs and improve the therapeutic index of drugs by increasing tumor vascular and tissue permeability However,there is no study about the efficacy of iRGD combining with radiotherapy.We mainly investigate the efficacy of iRGD combining with radiotherapy in inhibiting the growth of 4T1 tumor in vitro 3D tumor cell spheres and in vivo and explore the maybe corrdination mechanism between themMethods:3D tumor cell spheres of breast cancer were constructed,the growth of tumor cell spheres was observed by microscopy,and the anti-tumor effect of iRGD combining with irradiation was evaluated by the tumor cell volume and morphological changes.A mouse 4T1 breast trmor model was also constructed.iRGD were injected through tail vein on day 10.And tumors locally received one 5-Gy dose electron irradiation(IR)after 4 hours.The tumors were measured and monitored every 2 days.At the end of experiment,mice were sacrificed and the weight of tumors and spleens were measured.The kidney,heart and liver sections were fixed and stained with eosin-hematoxylin for safety evaluation.The population of myeloid-derived suppression cells(MDSCs)in the spleen and tumor of mice were respectively analyzed by flow cytometry.The cytokine in tumor tissue were measured by cytometric bead array(CBA).Results:We demonstrated in 3D tumor spheroids that compared with control group,IR along group or iRGD along group.The growth of tumor cell spheres was significantly impaired in the group receiving irradiation plus iRGD combination therapy.And in the mouse breast tumor model,the growth of tumor was significantly suppressed and the weights of tumor were reduced in the combination therapy group.Additionally,there were no obvious changes in H&E-stained kidney,heart and liver sections following treatment with combination therapy as compared to other groups.Flow cytometric analysis of MDSCs showed that MDSCs in spleen and tumor were reduced by combination therapy.Combination therapy with iRGD and irradiation exhibited the greatest effect on MDSC and further reduced the cytokine in tumors.Conclusion:Our work describes a previously uncharacterized mechanism by which iRGD enhances irradiation.Tumor-penetrating peptide enhances the effect of radiotherapy by down regulating the accumulation of suppressor cells in tumor tissue.Our findings could broaden the scope of current endeavors to enhance the effect of accurate radiotherapy and provide insight into the design of new therapeutics.