A novel HPV16 E7-affitoxin for targeted therapy of HPV16-induced human cervical cancer.
A novel HPV16 E7-affitoxin for targeted therapy of HPV16-induced human cervical cancer.
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一种新型 HPV16 E7-affitoxin，用于 HPV16 诱导的人宫颈癌的靶向治疗
DOI：
10.7150/thno.24607
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发表时间：
2018
期刊：
影响因子：
12.4
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Jiang P;Wang L;Hou B;Zhu J;Zhou M;Jiang J;Wang L;Chen S;Zhu S;Chen J;Zhang L
宫颈癌是全球女性癌症死亡的第二大常见原因，与高危人乳头瘤病毒 (HPV) 感染密切相关，尤其是最常见的基因型 HPV 16。迄今为止，尚无成熟的非侵入性疗法可治疗宫颈癌。方法：在这里，我们报告了一种针对 HPV16 E7 蛋白的新型 Affitoxin，HPV16 E7 蛋白是 HPV 诱导的宫颈癌分子靶向治疗的主要靶蛋白之一。亲和毒素 ZHPV16E7 affitoxin384 是通过将修饰的假单胞菌外毒素 A (PE38KDEL) 与 HPV16 E7 特异性亲和体融合而产生的。使用多种方法对表达和纯化的 ZHPV16E7 affitoxin384 进行了表征。分别进行SPR测定、间接免疫荧光测定和近红外（NIR）光学成像来评估ZHPV16E7 affitoxin384在体外和体内对HPV16 E7蛋白的靶向能力。使用细胞活力测定和SiHa荷瘤裸鼠分别评估ZHPV16 E7 affitoxin384的体外和体内功效。结果：体外SPR实验和间接免疫荧光实验表明ZHPV16E7 affitoxin384对HPV16 E7具有高结合亲和力和特异性。在 ZHPV16 E7 affitoxin384 存在的情况下，观察到 HPV16 阳性细胞的细胞活力显着降低。通过近红外光学成像，ZHPV16 E7 affitoxin384 特异性靶向体内 HPV16 阳性肿瘤。 ZHPV16E7 Affitoxin384 在两种荷瘤裸鼠模型中显示出显着的体内抗肿瘤功效。结论：ZHPV16E7 affitoxin384 是一种有效的抗宫颈癌治疗剂，可有效对抗人类 HPV16 阳性肿瘤。
Cervical cancer, the second most common cause of cancer death in women worldwide, is significantly associated with infection of high-risk human papillomaviruses (HPVs), especially the most common genotype, HPV 16. To date, there is no established noninvasive therapy to treat cervical cancer. Methods: Here, we report a novel affitoxin that targets HPV16 E7 protein, one of the primary target proteins in molecular targeted therapy for HPV-induced cervical cancer. The affitoxin, ZHPV16E7 affitoxin384 was generated by fusing the modified Pseudomonas Exotoxin A (PE38KDEL) to the HPV16 E7-specific affibody. The expressed and purified ZHPV16E7 affitoxin384 was characterized using numerous methods. SPR assay, indirect immunofluorescence assay, and near-infrared (NIR) optical imaging were respectively performed to assess the targeting ability of ZHPV16E7 affitoxin384 to HPV16 E7 protein both in vitro and in vivo. Cell viability assays and SiHa tumor-bearing nude mice were used to evaluate the efficacy of ZHPV16 E7 affitoxin384 in vitro and in vivo, respectively. Results: Using in vitro methods the SPR assay and indirect immunofluorescence assay showed that ZHPV16E7 affitoxin384 targeted HPV16 E7 with high binding affinity and specificity. Significant reduction of cell viability in HPV16 positive cells was observed in the presence of ZHPV16 E7 affitoxin384. By NIR optical imaging, ZHPV16 E7 affitoxin384 specifically targeted HPV16 positive tumors in vivo. ZHPV16E7 affitoxin384 showed significant in vivo antitumor efficacy in two kinds of tumor-bearing nude mouse models. Conclusions: ZHPV16E7 affitoxin384 is a potent anti-cervical cancer therapeutic agent that could be effective against HPV16 positive tumors in humans.