Photodynamic Stromal Depletion Enhances Therapeutic Nanoparticle Delivery in 3D Pancreatic Ductal Adenocarcinoma Tumor Models.
Photodynamic Stromal Depletion Enhances Therapeutic Nanoparticle Delivery in 3D Pancreatic Ductal Adenocarcinoma Tumor Models.
复制标题
光动力基质消耗增强 3D 胰腺导管腺癌肿瘤模型中的治疗性纳米颗粒递送。
DOI：
10.1111/php.13663
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发表时间：
2023
影响因子：
3.3
通讯作者：
Celli,JonathanP
中科院分区：
文献类型：
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作者：
Karimnia,Vida;Stanley,MElizabeth;Fitzgerald,ChristianT;Rizvi,Imran;Slack,FrankJ;Celli,JonathanP
胰腺导管腺癌是人类最致命的恶性肿瘤之一。PDAC的特征在于致密的纤维基质，其阻碍药物递送并发挥复杂的肿瘤促进作用。光动力疗法（PDT）是一种基于光的疗法，已被证明对胰腺肿瘤临床可行且有效。在这里，我们使用体外异细胞3D共培养模型结合成像，整体流变学和微流变学来研究PDAC基质的非细胞组分的光降解（光动力基质耗竭，PSD）。通过测量PDT前后细胞外基质（ECM）的流变学，我们发现ECM的软化伴随着纳米颗粒（NPs）转运的增加。同时，如我们先前所示，基质成纤维细胞的光破坏导致肿瘤对PDT的反应增强。在这里，我们特别评估了PSD增强RNA纳米药物递送的能力，使用携带miR-21 - 5 P抑制剂的NP，PDAC oncomiR。我们通过观察PDCD 4（miR-21 - 5 P的蛋白靶点）表达的增加证实了PSD后这种治疗性NP的递送改善。总的来说，3D肿瘤模型中的这些结果表明，可以开发PSD以增强其他癌症治疗剂的递送并改善肿瘤对治疗的反应。
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of human malignancies. PDAC is characterized by dense fibrous stroma which obstructs drug delivery and plays complex tumor‐promoting roles. Photodynamic therapy (PDT) is a light‐based modality which has been demonstrated to be clinically feasible and effective for tumors of the pancreas. Here, we usein vitroheterocellular 3D co‐culture models in conjunction with imaging, bulk rheology and microrheology to investigate photodegradation of non‐cellular components of PDAC stroma (photodynamic stromal depletion, PSD). By measuring the rheology of extracellular matrix (ECM) before and after PDT we find that softening of ECM is concomitant with increased transport of nanoparticles (NPs). At the same time, as shown by us previously, photodestruction of stromal fibroblasts leads to enhanced tumor response to PDT. Here we specifically evaluate the capability of PSD to enhance RNA nanomedicine delivery, using a NP carrying an inhibitor of miR‐21‐5P, a PDAC oncomiR. We confirm improved delivery of this therapeutic NP after PSD by observation of increased expression of PDCD4, a protein target of miR‐21‐5P. Collectively, these results in 3D tumor models suggest that PSD could be developed to enhance delivery of other cancer therapeutics and improve tumor response to treatment.