Modelling and breaking down the biophysical barriers to drug delivery in pancreatic cancer
Modelling and breaking down the biophysical barriers to drug delivery in pancreatic cancer
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DOI：
10.1039/d3lc00660c
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发表时间：
2024-01-19
期刊：
影响因子：
6.1
通讯作者：
Peyman，Sally A.
中科院分区：
文献类型：
--
作者：
Kpeglo，Delanyo;Haddrick，Malcolm;Peyman，Sally A.
胰腺导管腺癌 (PDAC) 基质及其固有的药物输送生物物理障碍是治疗耐药的核心。这使得 PDAC 成为最常见且预后不良的胰腺癌。化疗药物吉西他滨用于治疗各种实体瘤，包括胰腺癌，但对患者生存的影响不大。不断生长的 PDAC 肿瘤块具有高密度的细胞和细胞外基质 (ECM) 蛋白（即胶原蛋白），导致高间质压力，导致脉管系统塌陷和致密、缺氧、机械僵硬的基质，间质流量减少，这对药物输送到细胞至关重要。尽管如此，大多数药物研究都是在细胞模型上进行的，忽略了这些药物输送的生物物理障碍。微流控技术提供了一个有前途的平台，可以通过适当的流动条件和传输动力学来模拟肿瘤生物物理特征。我们提出了一种微流体 PDAC 培养模型，涵盖了疾病治疗的生物物理障碍，以评估血管紧张素 II 受体阻滞剂氯沙坦（已被发现具有基质消耗特性）在改善吉西他滨疗效方面的用途。将 PDAC 细胞接种到我们的 5 通道微流体装置中，进行 21 天的培养，以模拟刚性、胶原性 PDAC 基质，间质流量减少，这对于将药物输送到癌细胞以及评估吉西他滨和氯沙坦治疗至关重要。使用氯沙坦，我们的培养基质具有更多的孔隙和更少的胶原蛋白，导致培养间隙空间的水力传导率增加并改善吉西他滨的效果。我们证明了建模肿瘤生物物理障碍对于成功评估新药和递送方法的重要性。
The pancreatic ductal adenocarcinoma (PDAC) stroma and its inherent biophysical barriers to drug delivery are central to therapeutic resistance. This makes PDAC the most prevalent pancreatic cancer with poor prognosis. The chemotherapeutic drug gemcitabine is used against various solid tumours, including pancreatic cancer, but with only a modest effect on patient survival. The growing PDAC tumour mass with high densities of cells and extracellular matrix (ECM) proteins, i.e., collagen, results in high interstitial pressure, leading to vasculature collapse and a dense, hypoxic, mechanically stiff stroma with reduced interstitial flow, critical to drug delivery to cells. Despite this, most drug studies are performed on cellular models that neglect these biophysical barriers to drug delivery. Microfluidic technology offers a promising platform to emulate tumour biophysical characteristics with appropriate flow conditions and transport dynamics. We present a microfluidic PDAC culture model, encompassing the disease's biophysical barriers to therapeutics, to evaluate the use of the angiotensin II receptor blocker losartan, which has been found to have matrix-depleting properties, on improving gemcitabine efficacy. PDAC cells were seeded into our 5-channel microfluidic device for a 21-day culture to mimic the rigid, collagenous PDAC stroma with reduced interstitial flow, which is critical to drug delivery to the cancer cells, and for assessment with gemcitabine and losartan treatment. With losartan, our culture matrix was more porous with less collagen, resulting in increased hydraulic conductivity of the culture interstitial space and improved gemcitabine effect. We demonstrate the importance of modelling tumour biophysical barriers to successfully assess new drugs and delivery methods.