Experimental Study Of Novel Targeted Radionuclide Therapy In The Patient-derived Tumor Xenograft Models

Targeted Radionuclide Therapy(TRT),a branch of radiotherapy,is the use of radioisotopes to deliver ionization energy to tumor cells.Besides being utilized in the treatment of local tumors such as external radiotherapy,TRT can treat metastatic tumors through systemic administration.Patient-derived xenograft(PDX)models have great potential in drug development studies because they reliably reproduce the patient’s parental tumor for both IHC markers and genetic alterations as well as for evaluating the response to the corresponding therapeutic regimens,and become the most valuable preclinical model.Therefore,In our study we developed PDX models of non-small cell lung cancer(NSCLC)and neuroendocrine carcinomas(NECs),EB-RGD targeting αvβ3 and EB-TATE targeting SSTR were used as biological carriers for internal irradiation,with superior physical properties of diagnosis and integration of nuclide 177Lu as the treatment of radioactive nuclides,then we used to evaluate the imaging and therapeutic efficacy of two kinds of molecular probes.In our study,three groups of NSCLC-PDX models and one group of NECS-PDX models were successfully established,all of which maintained the same immunohistochemical and genetic characteristics of human primary tumors.In SPECT imaging and biodistribution studies,the accumulation of 177Lu-EB-RGD in PDXαvβ3+and PDXαvβ3-models was significantly higher than that of its corresponding monomone 177Lu-RGD.177Lu-EB-TATE had a longer retention time in NECs-PDX tumors.Both SPECT imaging and biodistribution results showed a higher tumor uptake,a therapy dose of 18.5 MBq 177Lu-EB-RGD may be strong enough for tumor elimination in the PDX models with intense integrin αvβ3 expression,and there was no evidence of tumor recurrence during the observation period.This treatment was also effective in PDXαvβ3-:29.6 MBq 177Lu-EB-RGD significantly delayed tumor growth compared to the control group or 177Lu-RGD.Although 177Lu-EB-TATE cannot completely eliminate tumors in NECs-PDX model mice,compared with normal saline,177Lu-TATE and EP chemotherapy,177Lu-EB-TATE has the effect of controlling and delaying tumor growth,and the dose of 29.6 MBq can achieve significant tumor control effect,no side effects of important organs such as kidney and bone marrow are observed after treatment.Preclinical data using the PDX models indicate that 177Lu-EB-RGD may be an effective treatment option for NSCLC,and 177Lu-EB-TATE may also be an effective treatment option for NECs with positive SSTR expression,based on EB derivatives.The new molecular probes are expected to provide new treatment strategies for patients with advanced tumors and should be further evaluated in clinical trials.