Massachusetts General Hospital and Harvard Medical School, Wellman Center for Photomedicine, Boston, Massachusetts 02114, United States.
Department of Chemistry, KAIST, Daejeon 34141, Republic of Korea.
Mol Pharm. 2022 Jul 4;19(7):2549-2563. doi: 10.1021/acs.molpharmaceut.2c00260. Epub 2022 May 18.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by increased levels of desmoplasia that contribute to reduced drug delivery and poor treatment outcomes. In PDAC, the stromal content can account for up to 90% of the total tumor volume. The complex interplay between stromal components, including pancreatic cancer-associated fibroblasts (PCAFs), and PDAC cells in the tumor microenvironment has a significant impact on the prognoses and thus needs to be recapitulated when evaluating various treatment strategies. This study is a systematic evaluation of photodynamic therapy (PDT) in 3D heterotypic coculture models of PDAC with varying ratios of patient-derived PCAFs that simulate heterogeneous PDAC tumors with increasing stromal content. The efficacy of antibody-targeted PDT (photoimmunotherapy; PIT) using cetuximab (a clinically approved anti-EGFR antibody) photoimmunoconjugates (PICs) of a benzoporphyrin derivative (BPD) is contrasted with that of liposomal BPD (Visudyne), which is currently in clinical trials for PDT of PDAC. We demonstrate that both Visudyne-PDT and PIT were effective in heterotypic PDAC 3D spheroids with a low stromal content. However, as the stromal content increases above 50% in the 3D spheroids, the efficacy of Visudyne-PDT is reduced by up to 10-fold, while PIT retains its efficacy. PIT was found to be 10-, 19-, and 14-fold more phototoxic in spheroids with 50, 75, and 90% PCAFs, respectively, as compared to Visudyne-PDT. This marked difference in efficacy is attributed to the ability of PICs to penetrate and distribute homogeneously within spheroids with a higher stromal content and the mechanistically different modes of action of the two formulations. This study thus demonstrates how the stromal content in PDAC spheroids directly impacts their responsiveness to PDT and proposes PIT to be a highly suited treatment option for desmoplastic tumors with particularly high degrees of stromal content.
胰腺导管腺癌（PDAC）是一种侵袭性疾病，其特征是细胞外基质增多，这导致药物输送减少和治疗效果不佳。在 PDAC 中，基质含量可占肿瘤总体积的 90%。肿瘤微环境中基质成分（包括胰腺癌相关成纤维细胞 [PCAFs]）与 PDAC 细胞之间的复杂相互作用对预后有重大影响，因此在评估各种治疗策略时需要进行重现。本研究系统性评估了 PDT 在具有不同患者来源的 PCAFs 比例的 PDAC 异质 3D 共培养模型中的作用，这些模型模拟了基质含量逐渐增加的异质性 PDAC 肿瘤。我们比较了使用西妥昔单抗（一种临床批准的抗 EGFR 抗体）作为 PDT 的抗体靶向治疗（photoimmunotherapy；PIT）与目前正在进行 PDAC PDT 临床试验的脂质体 BPD（Visudyne）的疗效。我们证明，在基质含量低的异质 PDAC 3D 球体中，Visudyne-PDT 和 PIT 均有效。然而，当 3D 球体中的基质含量增加到 50%以上时，Visudyne-PDT 的疗效降低了 10 倍，而 PIT 则保持其疗效。与 Visudyne-PDT 相比，在含有 50%、75%和 90% PCAFs 的球体中，PIT 的光毒性分别提高了 10 倍、19 倍和 14 倍。这种疗效的显著差异归因于 PICs 能够穿透并均匀分布在基质含量较高的球体中，以及两种制剂作用机制的不同。因此，本研究表明 PDAC 球体中的基质含量如何直接影响其对 PDT 的反应性，并提出 PIT 是治疗具有特别高基质含量的纤维瘤的高度适宜的治疗选择。
