Endocrine Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Department of Surgery, Albert Einstein College of Medicine, Bronx, NY.
J Natl Cancer Inst. 2018 Sep 1;110(9):1019-1029. doi: 10.1093/jnci/djy003.
The advantages of nanomedicines include preferential delivery of the payload directly to tumor tissues. CYT-21625 is the novel, first-in-class gold nanomedicine designed to target tumor vasculature and cancer cells by specifically delivering recombinant human tumor necrosis factor alpha (rhTNF) and a paclitaxel prodrug.
We analyzed TNF receptor expression in publicly available gene expression profiling data and in thyroid tissue samples. Mice with metastatic FTC-133 and 8505C xenografts and the MEN1 conditional knock-out mice were treated weekly with CYT-21625 and gold nanoparticles with rhTNF only (CYT-6091); controls included mice treated with either paclitaxel or saline. In vivo luciferase activity was used to assess the effects on tumor growth. Computed tomography, magnetic resonance imaging, and 18F-Fludeoxyglucose positron emission tomography were used to study tumor selectivity in mice with insulin-secreting pancreatic neuroendocrine tumors (PNETs). All statistical tests were two-sided.
Anaplastic thyroid cancer (ATC) expressed statistically significantly higher levels of TNF receptor superfamily 1A and 1B messenger RNA (n = 11) and protein (n = 6) than control samples (n = 45 and 13, respectively). Mice (n = 5-7 per group) with metastatic ATC (P < .009) and FTC-133 xenografts (P = .03 at week 3, but not statistically significant in week 4 owing to reduced sample size from death in non-CYT-21625 groups) treated with CYT-21625 had a statistically significantly lower tumor burden. Treatment with CYT-21625 resulted in loss of CD34 expression in intratumoral vasculature, decreased proliferating cell nuclear antigen, and increased cleaved caspase-3. Intratumoral vascular leakage occurred only in mice with PNET and ATC treated with CYT-6091 and CYT-21625. CYT-6091 and CYT-21625 preferentially deposited in PNETs and statistically significantly decreased serum insulin levels (n = 3 per group, P < .001). There were no toxicities observed in mice treated with CYT-21625.
CYT-21625 is effective in mice with PNETs and metastatic human thyroid cancer with no toxicities. Thus, CYT-21625 should be studied in patients with advanced PNETs and thyroid cancer.
纳米医学的优势包括将有效载荷直接递送到肿瘤组织。CYT-21625 是一种新型的、首创的金纳米药物，旨在通过特异性地递送达重组人肿瘤坏死因子 α（rhTNF）和紫杉醇前药来靶向肿瘤血管和癌细胞。
我们分析了公开的基因表达谱数据和甲状腺组织样本中 TNF 受体的表达。具有转移性 FTC-133 和 8505C 异种移植的小鼠和 MEN1 条件敲除小鼠每周用 CYT-21625 和仅含 rhTNF 的金纳米颗粒（CYT-6091）治疗；对照组包括用紫杉醇或生理盐水治疗的小鼠。体内荧光素酶活性用于评估对肿瘤生长的影响。计算机断层扫描、磁共振成像和 18F-氟脱氧葡萄糖正电子发射断层扫描用于研究胰岛素分泌胰腺神经内分泌肿瘤（PNETs）小鼠的肿瘤选择性。所有统计检验均为双侧检验。
间变性甲状腺癌（ATC）mRNA（n=11）和蛋白（n=6）水平均明显高于对照组样本（n=45 和 13）。转移性 ATC（P<.009）和 FTC-133 异种移植小鼠（P=0.03 周 3，但由于非 CYT-21625 组死亡导致样本量减少，第 4 周统计学上无显著性差异）组，用 CYT-21625 治疗的小鼠肿瘤负荷明显降低。用 CYT-21625 治疗导致肿瘤内血管中 CD34 表达丧失、增殖细胞核抗原减少和 cleaved caspase-3 增加。仅在接受 CYT-6091 和 CYT-21625 治疗的 PNET 和 ATC 小鼠中观察到肿瘤内血管渗漏。与 CYT-6091 和 CYT-21625 相比，CYT-6091 和 CYT-21625 优先沉积在 PNET 中，并使血清胰岛素水平显著降低（每组 3 只小鼠，P<.001）。用 CYT-21625 治疗的小鼠未观察到毒性。
CYT-21625 在 PNETs 和转移性人类甲状腺癌小鼠中有效，且无毒性。因此，CYT-21625 应在晚期 PNETs 和甲状腺癌患者中进行研究。
