Background: Pancreatic ductal adenocarcinoma (PDAC), which has a poor prognosis, involves an overabundance of fibroblasts and extracellular matrix. Cancer-associated fibroblasts (CAFs) are critical for providing structural support by secreting soluble factors and extracellular matrix proteins into the stroma. We assessed the potential of near-infrared photoimmunotherapy (NIR-PIT) targeting CAFs in PDAC.Methods: PDAC cells (Capan-1 and SUIT-2) and CAFs (hPSC-5) were used. Anti-human fibroblast activation protein (FAP)/podoplanin (PDPN) antibodies were used to bind to CAFs and conjugates with the specific photosensitizer IRDye®700DX (IR700) to investigate the effects of NIR-PIT. Thereafter, BALB/c Slc-nu/numice were transplanted with Capan-1 and/or CAFs and treated with gemcitabine (GEM) with or without NIR-PIT.Results: The binding rate of anti-FAP antibody-AlexaFluor®488 conjugate to hPSC-5 cells was high, whereas that of the anti-PDPN antibody-conjugate was not. The incubation of anti-FAP antibody-IR700 conjugate (αFAP-IR700) with hPSC-5 cells for 3 h led to maximal fluorescence on the surface of hPSC-5 cells. When NIR-PIT with αFAP-IR700 was performed in the co-culture group of Capan-1 and hPSC-5 cells, the proliferative capacity of Capan-1 cells decreased to the same level as that when Capan-1 cells were cultured alone (p< 0.05). In vivo, compared with the GEM group, the NIR-PIT with the GEM group showed a significant reduction in the tumor volume (day 28: 79 vs. 382 mm3,p< 0.05). Tumor volumes in the NIR-PIT group were not reduced compared with those in the control group.Conclusions: Combining NIR-PIT with conventional chemotherapy to target CAFs may enhance the anticancer effects on PDAC.
背景：胰腺导管腺癌（PDAC）预后不良，其肿瘤微环境中存在大量成纤维细胞和细胞外基质。癌症相关成纤维细胞（CAFs）通过向基质分泌可溶性因子和细胞外基质蛋白，对肿瘤结构支持至关重要。本研究评估了靶向CAFs的近红外光免疫疗法（NIR-PIT）在PDAC治疗中的潜力。 方法：采用PDAC细胞系（Capan-1和SUIT-2）及CAFs细胞（hPSC-5）。使用抗人成纤维细胞活化蛋白（FAP）/平足蛋白（PDPN）抗体与CAFs结合，并与特异性光敏剂IRDye®700DX（IR700）偶联，以探究NIR-PIT的效应。随后，将Capan-1细胞和/或CAFs移植至BALB/c Slc-nu/nu小鼠体内，并给予吉西他滨（GEM）联合或不联合NIR-PIT治疗。 结果：抗FAP抗体-AlexaFluor®488偶联物与hPSC-5细胞的结合率较高，而抗PDPN抗体偶联物则未显示明显结合。抗FAP抗体-IR700偶联物（αFAP-IR700）与hPSC-5细胞孵育3小时后，细胞表面荧光强度达到峰值。在Capan-1与hPSC-5细胞共培养组中，使用αFAP-IR700进行NIR-PIT后，Capan-1细胞的增殖能力下降至与单独培养Capan-1细胞时相当的水平（p<0.05）。体内实验显示，与单纯GEM治疗组相比，NIR-PIT联合GEM治疗组的肿瘤体积显著减小（第28天：79 vs. 382 mm³，p<0.05）。而单纯NIR-PIT组与对照组相比，肿瘤体积未见明显缩小。 结论：靶向CAFs的NIR-PIT联合传统化疗可能增强对PDAC的抗癌效果。
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