基于多肽RGD/TMTP2双重靶向乳腺癌分子探针设计合成和实验研究

Tumor invasion and metastasis is the leading cause of death in cancer patients, blood and lymphatic metastasis of cancer cells is the main way to metastasize to distant organs. Regional lymph node metastasis can be considered as an early signal of tumor metastasis, and it is used to predict the prognosis of cancer patients or as a basis for determining the treatment regimen. RGD peptide is a cyclic peptide composed of five amino acids, which is capable of targeting angiogenesis by combining with integrin avb3 receptor. TMTP2 is a polypeptide screened by flagella displayed peptide library and its core region consists of five amino acids. It can combine with VGEFR3, which is a marker of lymphangiogenesis. In this application by using CADD， we tried to design a novel SPECT imaging agent, 99mTc-HYINC/EDDA-E3-RGD/TMTP2, was synthesized for targeting breast tumor and metastases.RGD-TMTP2 can target nascent tumor lymphatic and blood vessels, which can be mark Radionuclides 99mTc using bifunctional chelating agents (HYNIC),SPECT images was carried out Orthotopic tumor-bearing mouse model of breast cancer.

肿瘤的侵袭和转移是癌症患者死亡的重要原因之一,血道和淋巴道转移是癌细胞形成远处转移的主要途径。肿瘤细胞转移至局部淋巴结可被视为肿瘤转移的早期信号,常用来预测肿瘤患者的预后或作为确定治疗方案的依据。RGD多肽是有五个氨基酸组成的环肽，其能够与整合素受体 a v b 3相结合从而能够靶向于新生血管；TMTP2是通过鞭毛肽库展示技术筛选出的核心区域为五个氨基酸的多肽，其能够结合新生淋巴管的标记VGEFR3。本研究拟采用CADD技术方法设计寻找一种能够对乳腺癌原发灶及淋巴转移灶特异显像的SPECT显像剂99mTc-HYINC/EDDA-E3-RGD/TMTP2，RGD-TMTP2能够靶向肿瘤新生的淋巴管及血管，通过双功能螯合剂HYNIC将RGD-TMTP2标记放射性核素，利用SPECT对乳腺癌原位荷瘤小鼠模型进行显像。

肿瘤的侵袭和转移是癌症患者死亡的重要原因之一,血道和淋巴道转移是癌细胞形成远处转移的主要途径。肿瘤细胞转移至局部淋巴结可被视为肿瘤转移的早期信号,常用来预测肿瘤患者的预后或作为确定治疗方案的依据。TMVP1是通过鞭毛肽库展示技术筛选出的核心区域为五个氨基酸的多肽，其能够结合新生淋巴管的标记的VEGFR-3。.A 设计合成核医学分子探针99mTc-HYINC/EDDA-E3-RGD/TMVP1。乳腺癌4T1皮下荷瘤小鼠，体内分布试验显示99mTc-HYNIC-E3-RGD/TMVP1具有靶向性，T/血液在90分钟比率最高；SPECT显像显示在90分钟时显像效果较好T/NT=4.2。体内分布及SPECT 均显示肾脏放射性浓聚。 .B 设计合成核医学分子探针68Ga-DOTA-TMVP1。与LEC（shVEGFR-3）和HUVECs相比，68Ga-DOTA-MVP1对于LECs具有更高的结合能力。人子宫颈癌细胞C33-A皮下荷瘤小鼠,体内分布试验显示68Ga-DOTA-TMVP1具有靶向性，并且T/血液和T/肌肉在60分钟时的比率最高。人子宫颈癌细胞C33-A和卵巢癌SKOV-3皮下荷瘤小鼠，120min时间点，C33-A和SKOV-3肿瘤的T/N分别为3.58±0.31和4.98±0.28。体内分布及PET均显示肾脏放射性浓聚。.TMVP1在核医学领域是具有广泛发展前景的分子影像探针。