Dwairy Mutaz, Yehya Alaa, Mohammad Feras M, Alzoubi Hiba
Department of Civil Engineering, Yarmouk University, Irbid, Jordan.
Department of Biomedical Systems and Informatics Engineering, Yarmouk University, Irbid, Jordan.
PLoS One. 2025 Jul 11;20(7):e0328196. doi: 10.1371/journal.pone.0328196. eCollection 2025.
Tumor stiffness is a critical factor influencing cancer progression, therapeutic resistance, and drug delivery. This study investigates the role of mechanical normalization in breast cancer therapy through the anti-fibrotic action of losartan, an angiotensin II type 1 receptor blocker. We developed a comprehensive multiphysics model integrating tumor cell proliferation, oxygen transport, interstitial fluid dynamics, and losartan pharmacokinetics/pharmacodynamics (PK/PD). Simulations demonstrate that losartan reduces tumor stiffness by up to 28%, enhances oxygenation by 8%, and increases tumor porosity by ~45%, thereby enhancing drug penetration and interstitial transport. Furthermore, tumor cell concentration decreased by 88%, reflecting the drug's dual anti-proliferative and pro-apoptotic effects. Spatial analyses revealed heterogeneity in stiffness reduction and drug response, emphasizing the importance of tumor geometry and perfusion. Our findings support the potential of losartan as a mechanotherapeutic adjuvant to enhance standard cancer treatments by remodeling the tumor microenvironment and overcoming mechanical barriers to therapy.
肿瘤硬度是影响癌症进展、治疗抗性和药物递送的关键因素。本研究通过血管紧张素II 1型受体阻滞剂氯沙坦的抗纤维化作用，研究了机械归一化在乳腺癌治疗中的作用。我们开发了一个综合多物理模型，该模型整合了肿瘤细胞增殖、氧气运输、间质液动力学和氯沙坦的药代动力学/药效学（PK/PD）。模拟结果表明，氯沙坦可使肿瘤硬度降低多达28%，使氧合增加8%，并使肿瘤孔隙率增加约45%，从而增强药物渗透和间质运输。此外，肿瘤细胞浓度降低了88%，反映了该药物的双重抗增殖和促凋亡作用。空间分析揭示了硬度降低和药物反应的异质性，强调了肿瘤几何形状和灌注的重要性。我们的研究结果支持氯沙坦作为一种机械治疗辅助药物的潜力，通过重塑肿瘤微环境和克服治疗的机械障碍来增强标准癌症治疗。
