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南京大学叶德举领衔《JACS》|“智能开关”纳米探针!让结直肠癌手术中“肿瘤发光”,精准切除不留遗憾!

  • 2026-05-09 11:42:41
南京大学叶德举领衔《JACS》|“智能开关”纳米探针!让结直肠癌手术中“肿瘤发光”,精准切除不留遗憾!
作者简介
WINTER IS COMING

本次分享一篇2026年 4月发表在 JACS 上的文章,该文章的第一位通讯作者为南京大学化学与化工学院的叶德举教授主要研究方向为发展多模态分子影像探针的构筑方法学研究、发展靶向型诊疗探针应用于成像指导下的疾病干预研究等

1
 研究背景

结直肠癌是全球高发的恶性肿瘤,手术切除是主要根治手段。然而,传统手术依赖医生肉眼观察和触觉判断,微小病灶、腹膜转移灶、淋巴结微转移往往难以发现,导致术后复发风险居高不下。

术中荧光导航技术近年来快速发展,但现有“always-on”型荧光探针(如吲哐菁绿ICG)缺乏肿瘤特异性,容易在正常组织中产生背景信号,肿瘤-背景比(TBR)不理想,难以精准界定肿瘤边界。

如何让荧光只在癌细胞中“点亮”,而正常组织保持“黑暗”?

2
研究亮点

传统“单锁”探针只响应一个肿瘤标志物,容易被正常组织中的低水平信号干扰。而duNP-DA采用了“AND逻辑门”设计:

条件1:细胞外酸性肿瘤微环境(pH ~6.5)

条件2:细胞内高浓度硫化氢(H₂S)      条件3:溶酶体酸性环境(pH ~5.0)

三个条件必须同时满足,荧光才会被激活——这就像三道锁的门,只有真正的肿瘤细胞才能“全部打开”。

静脉注射后,duNP-DA带负电,血液循环时间长,正常组织摄取极低

到达肿瘤部位后,酸性微环境触发DA水解,表面电荷由负转正(zeta电位从-29.9 mV升至+2.8 mV)

正电荷促进细胞内吞,同时静电富集HS⁻离子,加速H₂S反应

进入溶酶体后,H₂S还原EM 1²⁺(解除FRET猝灭),同时酸性pH激活IR-N荧光

800 nm近红外荧光“爆发式”点亮,增强超过100倍!

设计策略

3
研究成果

注射duNP-DA后24小时,肿瘤荧光达峰值,TBR高达8.2

对比单响应探针pH-moNP-DA(TBR≈1.8)和H₂S-moNP-DA(TBR≈1.7),优势显著

可检测的最小肿瘤体积仅~5.4 mm³,TBR仍达2.7

成功实现<3 mm微小肿瘤的荧光引导精准切除,病理证实切缘干净

在CT-26-Luc原位结直肠癌模型中,duNP-DA荧光与生物发光高度吻合,TBR=5.1

可检出直径仅~2 mm的腹膜微小转移灶

在荧光引导下,成功切除肉眼不可见的深部腹膜转移结节(术中视频记录)

4
关键数据

首先,作者验证了duNP-NH₂的核心性能——EM 1²⁺对H₂S具有快速二级反应动力学(~9780 M⁻¹s⁻¹),IR-N在pH  5.0时荧光增强68倍,且该探针仅在H₂S与酸性pH同时存在时才激活荧光(>100倍增强),并在细胞水平实现了H₂S高表达肿瘤细胞的特异性成像。

图1 

其次,展示了duNP-DA的电荷反转特性——在酸性pH 6.5下zeta电位从-29.9 mV升至+2.8 mV,H₂S反应速率加快至6050 M⁻¹s⁻¹,且酸性微环境可将肿瘤细胞摄取提升约4倍。

图2

接下来,在皮下HCT116荷瘤小鼠模型中,duNP-DA实现了高达8.2的肿瘤-背景比(TBR),可检测小至~5.4 mm³的微小肿瘤,并成功荧光引导下切除<3 mm的肿瘤病灶。

图3

随后,在原位和腹膜转移结直肠癌小鼠模型中,duNP-DA实现了TBR达5.1的肿瘤特异性成像,可检出直径仅2 mm的腹膜微小转移灶,并成功荧光引导下切除肉眼不可见的深部转移结节。

图4

接着,在临床结直肠癌标本中,duNP-DA能清晰区分原发灶(TBR≈3.7)、淋巴结转移(TBR≈3.1)和大网膜转移(TBR≈4.1),与H&E染色结果高度一致。

图5

最后,在22例临床标本的单盲验证中,duNP-DA区分肿瘤与正常组织的灵敏度和特异性均达100%,且荧光强度与AI量化肿瘤细胞密度呈强正相关(Pearson r = 0.9103)。

图6

5
总结与展望

总之,作者不仅在动物模型中验证了卓越的成像性能,更在临床标本盲测中取得了100%的准确性,距离临床转化仅一步之遥。

📣纳米智研

纳智见,研未来!专注纳米技术与智能医疗前沿!欢迎投稿与商务合作,敬请添加纳米智研主编微信!

论文链接DOI: 10.1021/jacs.6c04349External Link

期刊影响因子: 15.6

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原文链接点击阅读原文

声明:本文对研究论文的解读仅出于传播和交流肿瘤治疗领域学术进展的目的,旨在为读者提供前沿科研动态参考。文章内容不代表对原始文献数据真实性、科学性及临床适用性的判断或背书。读者如需引用或进一步验证,请务必查阅论文原文以获取完整信息。研究的具体临床应用需以后续权威机构评估结果为准。

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  1. CONNECT:[ UseTime:0.000756s ] mysql:host=127.0.0.1;port=3306;dbname=b460;charset=utf8mb4
  2. SHOW FULL COLUMNS FROM `fenlei` [ RunTime:0.000638s ]
  3. SELECT * FROM `fenlei` WHERE `fid` = 0 [ RunTime:0.000343s ]
  4. SELECT * FROM `fenlei` WHERE `fid` = 63 [ RunTime:0.005316s ]
  5. SHOW FULL COLUMNS FROM `set` [ RunTime:0.000615s ]
  6. SELECT * FROM `set` [ RunTime:0.000238s ]
  7. SHOW FULL COLUMNS FROM `article` [ RunTime:0.000590s ]
  8. SELECT * FROM `article` WHERE `id` = 537217 LIMIT 1 [ RunTime:0.001319s ]
  9. UPDATE `article` SET `lasttime` = 1779762532 WHERE `id` = 537217 [ RunTime:0.008881s ]
  10. SELECT * FROM `fenlei` WHERE `id` = 65 LIMIT 1 [ RunTime:0.000283s ]
  11. SELECT * FROM `article` WHERE `id` < 537217 ORDER BY `id` DESC LIMIT 1 [ RunTime:0.000713s ]
  12. SELECT * FROM `article` WHERE `id` > 537217 ORDER BY `id` ASC LIMIT 1 [ RunTime:0.000648s ]
  13. SELECT * FROM `article` WHERE `id` < 537217 ORDER BY `id` DESC LIMIT 10 [ RunTime:0.000981s ]
  14. SELECT * FROM `article` WHERE `id` < 537217 ORDER BY `id` DESC LIMIT 10,10 [ RunTime:0.000897s ]
  15. SELECT * FROM `article` WHERE `id` < 537217 ORDER BY `id` DESC LIMIT 20,10 [ RunTime:0.003820s ]
0.163247s