125碘/131碘混合标记肿瘤导向肽CRMP用于肿瘤靶向治疗的基础研究

Interstitial brachytherapy aims for a highly localized devitalisation of a well-defined treatment quantity in patient's body, thereby avoiding damage of surrounding non-neoplastic tissues. A low dose rates of < 100cGy/h irradiation could increase the therapeutic ratio as the ongoing repair of sublethal irradiation doses, which is more effective in non-neoplastic tissue than that in tumor. Iodine-125 implants generate a typically extreme dose inhomogeneity within target volumes which ranges from highly necrotizing doses surrounding the seeds to the ultimate form of fractionation at the peripheryof target volumes. However, the short of penetrating capability and limited radiation radius, iodine-125 requires much more powerful tumor-specific penetrating vectors. Tumor-homing peptides could specifically bind to tumors with high affinity and specificity. Therefore, these peptides have been developed as potential diagnostic tools for tumor mass imaging. Recently, one kind of novel cyclic tumor-homing peptides, named as C-end rule motif peptides (CRMP), was reported to be capable of enhancing the tumor penetration of peptides, chemicals, and biological nanoparticles into tumor tissues through a cryptic C-terminal rule (CendR) motif (R/KXXR/K-OH). After tumor binding based on the tumor-homing sequences, aproteolytic cleavage by undefined host proteases exposes the CendR motif, which is now able to interact with neuropilin-1 (NRP-1), activating a tissue-penetration pathway that delivers the peptide along with attached or co-administered payload into the tumor mass. This strategy allows the activation of the CendR motif only in a targeted tissue, avoiding NRP-1 activation in normal vasculature. Based on the above, we hypothesize these CRMP could also have potential to target delivery of radioisotopes such as iodine-125 and iodine-131, and induce more effective and specific therapeutic efficacy of iodine-125/iodine-131. If that is the case, we may develop more translational proposals in cancer diagnostic and therapeutic fields.

微创植入碘-125粒子进行肿瘤近距离局部放射治疗已成为治疗恶性肿瘤的一种有效技术，然而碘-125需要进入肿瘤细胞内才能发挥最大的杀伤作用，现有临床碘-125植入多采用玻璃，金属粒子等缺乏肿瘤靶向性及肿瘤穿透性的材料作为碘-125载体，影响碘-125持续低剂量辐射功效的发挥。 利用一类具有肿瘤特异性穿透能力的小分子CRMP（C-end rule motif peptide）多肽作为碘-125的载体，不但能使药物高效特异的结合到肿瘤表面，还能有效的将125I转运到肿瘤细胞内，更好的发挥碘-125对肿瘤细胞的杀伤能力。 本课题拟使用CRMP多肽作为放射性同位素碘-125及碘-131的载体，利用碘-131作为体内实时显像与初期冲击治疗分子，碘-125作为低能伽玛射线低剂量率连续照射杀伤分子，推出新型、高效、低毒副作用的碘-125/碘131混合标记放射性抗肿瘤多肽，为肿瘤放射性靶向治疗提供新的方法和途径。

肿瘤靶向多肽引导下的放射性核素诊断及治疗是近年来核医学研究的热点，本课题在执行中，设计并验证了一系列肿瘤靶向肽，用于碘131/碘125放射性标记的方法，及其用于核医学显像及治疗的研究。. 首先，我们合成了一种具有C末端R/KXXR/K特征，靶向神经纤毛蛋白-1（Neuropilin-1，NRP-1）的多肽CRMP-1，放射性碘标记率可达95%，并在非小细胞肺癌的动物模型上取得了良好的SPECT/CT显像效果，相关结果已提交申请专利一项。在此基础上，我们后续又设计并合成了几类双靶向多肽，除保留NRP-1靶向序列之外还增加了新的抗肿瘤靶点，如CD133，CD13，肿瘤新生血管等，进一步增强多肽载体对肿瘤的选择性。其不仅可用于放射性碘标记，还可用于α核素At-211的标记及NSCLC肿瘤治疗，为肿瘤靶向多肽开辟了新的潜在临床应用领域。此外，我们还发现研究中的放射性碘标记方法在改良后，可用于新型放射性微球的标记，我们自主开发的新型碘放射性标记可生物降解复合微球在大鼠原位肝癌的介入治疗中取得了良好的效果，将大鼠的生存期从19±7d延长到28±15d，相关结果已申请专利一项，并已进入实质性审查阶段。

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