TNYL Peptide Modified Micelle-gold Nanoparticles-drug Nanohybrid System For Combined Chemo-photothermal Treatment Of Orthotopic Colon Cancer

In recent years,it is well known that EphB4 receptor,a major member of Eph family of receptor tyrosine kinases,is over-expressed on cell membrane of numerous tumors and participates in various pathological process including tumor progression and angiogenesis which has been proved to be an effective therapeutic target in cancer therapy.In addition,some studies have shown that TNYL polypeptides(TNYLFSPNGPIARAW)could selectively combine with EphB4 receptors.In this thesis,we have constructed a kind of TNYL peptide-modified micelle(HP-TCS)which simultaneously loaded with paclitaxel(PTX)and hollow gold nanoparticles(HAuNS).HP-TCS could selective combine with EphB4 receptors under the mediation of TNYL peptide,and the PTX loaded in HP-TCS could also be accumulated in the tumor region at the same time.Under the irradiation of near-infrared(NIR)laser,HAuNS in the micelles absorbs near-infrared light,efficiently converts it into heat energy and triggers the release of PTX in the micelles,achieving a combined therapeutic effect on cancer chemotherapy and photothermotherapy.In order to evaluate the antitumor efficiency and clinical application of HP-TCS more effectively,,we established the orthotopic colon tumor model which ismore closer to the actual clinical treatment situation and highly expressed EphB4 receptors.First,we establish the visualized orthotopic CT26-Luc colon cancer model with bioluminescent colon cancer cells expressing the luciferase.After the mice with orthotopic colon tumor were intraperitoneal injected with D-fluorescein,the luminescent of CT26-Luc tumor cells which is detected by the bioluminescent image analysis system is fully overlap with the tumor region,and the Ki67 and HE tissue staining result of the tumor slides also proved the successful establishment of the visualized orthotopic tumor model.The biodistribution of ICG-labeled HP-TCS micelles was determined and the results showed that the micelles could specifically accumulate in the EphB4 receptor-expressing in situ CT26-Luc colon tumor.This provides the possibility of the subsequent combined photothermal and chemotherapy on in situ colon cancer.Then the antitumor pharmacodynamic study of HP-TCS in vivo was studied.BABL/C mice with orthotopic CT26-Luc tumor were intravenously injected with saline,PTX or HP-TCS,respectively.At 24 hours post injection,the laser fiber is inserted into the tumor under the guidance of a B ultrasound imaging equipment,and the in situ tumor received the near-infrared laser irradiation.The results showed,the group of HP-TCS plus laser irradiation(1.0 W/cm2,1min)exhibited the most excellent antitumor efficiency compared to the other groups.the tumors in this group atrophied obviously,which is due to the combined photothermal therapy and chemotherapy.