Purpose

Surgical excision of metastases is the only curative treatment strategy in peritoneal carcinomatosis management, and the completeness of tumor resection determines the success of the surgery. Tumor-specific fluorescence-guided probes can improve the outcomes of cytoreductive surgery and thereby prognosis. This study aimed to develop and evaluate the feasibility of fluorescently labeled ultrasmall porous silica nanoparticles (UPSN) for image-guided resection of peritoneally disseminated tumors of different origins.

Methods

Ultrasmall fluorescent nanoprobes were synthesized and characterized for their physicochemical properties and stability. Tumor-specific uptake and biodistribution profiles were evaluated in syngeneic CT26 colorectal and KPC-689 pancreatic cancer murine models. The practicability of real-time optical UPSN-guided resection was examined in the CT26 colorectal cancer model using a surgical stereomicroscope. Quantitative measurements of tumor sensitivity and specificity were performed. Histopathological examination validated in vivo findings about tumor-specific accumulation and safety of ultrasmall fluorescent probes.

Results

As-synthesized UPSNs were successfully surface modified with Cy5 or Cy3 dyes maintaining sub-15 nm size and near neutral charge which is beneficial for optimized in vivo pharmacokinetics. UPSN-Cy5 demonstrated high tumor-specific uptake and favorable biodistribution profiles in peritoneal metastasis models of CT26 and KPC tumors. Dye-conjugated UPSN enabled resection of microscopic lesions and achieved a higher tumor-to-background ratios in comparison to FDA-approved indocyanine green (ICG) dye in both models. Microscopic evaluation showed tumor localization and off-target safety profile of the UPSN-Cy5.

Conclusion

Ultrasmall fluorescent probes were effective in surgical resection of peritoneal metastases with high sensitivity and specificity, thus emerging as promising tumor agnostic agents for image-guided cancer surgery.

中文翻译：

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与肿瘤无关的超小纳米探针用于腹膜转移中荧光引导手术切除

 目的

手术切除转移灶是腹膜癌病管理中唯一的根治性治疗策略，肿瘤切除的完整性决定了手术的成功与否。肿瘤特异性荧光引导探针可以改善细胞减灭术的结局，从而改善预后。本研究旨在开发和评估荧光标记的超小多孔二氧化硅纳米颗粒 （UPSN） 用于图像引导切除不同来源的腹膜播散性肿瘤的可行性。

 方法

合成了超小荧光纳米探针，并对其物理化学性质和稳定性进行了表征。在同基因 CT26 结直肠癌和 KPC-689 胰腺癌小鼠模型中评估肿瘤特异性摄取和生物分布谱。使用外科立体显微镜在 CT26 结直肠癌模型中检查实时光学 UPSN 引导切除术的实用性。进行肿瘤敏感性和特异性的定量测量。组织病理学检查验证了关于超小荧光探针的肿瘤特异性积累和安全性的体内发现。

 结果

合成的 UPSN 用 Cy5 或 Cy3 染料成功进行表面修饰，保持亚 15 nm 大小和接近中性电荷，有利于优化体内药代动力学。UPSN-Cy5 在 CT26 和 KPC 肿瘤的腹膜转移模型中表现出高肿瘤特异性摄取和良好的生物分布谱。在两种模型中，与 FDA 批准的吲哚菁绿 （ICG） 染料相比，染料偶联的 UPSN 能够切除微观病灶，并实现了更高的肿瘤背景比。显微镜评估显示 UPSN-Cy5 的肿瘤定位和脱靶安全性。

 结论

超小荧光探针在腹膜转移的手术切除中有效，具有高敏感性和特异性，因此成为图像引导癌症手术中很有前途的肿瘤不可知药物。