Biophysics of cancer: modelling and assessing physical resistance to therapy

癌症的生物物理学：建模和评估身体对治疗的抵抗力

• 批准号: EP/V026739/1
• 负责人: Sally Peyman
• 金额: $ 43.75万
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FV026739%2F1
• 关键词: Biophysics; cancer; modelling; assessing; physical

This proposal will use organ-on-chip technology and Atomic Force Microscopy (AFM) to investigate the mechanical properties of in vitro cultured microtumours of pancreatic cancer as they develop under physiologically relevant flow conditions and how the mechanical stiffness of these tumours relates to drug resistance. Solid tumours develop in the body to form areas of dense, rigid tissue, similar to that of scar tissue. Within tumours, there is a complex microenvironment of biophysical conditions that determine the progression of the disease and provide physical barriers to drug delivery. Pancreatic cancer is hallmarked by a dense, fibrous tumour mass in which solid stress and hydraulic pressure cause the collapse of blood vessels, the main route for drug delivery. In addition, the high internal pressures act against the movement of drugs into the tumour mass. Yet despite these critically important physical factors, most in vitro testing of drugs is done against cell culture models that neglect these biophysical parameters entirely. This proposal we will create microtumours of pancreatic cancer by using microfluidic droplet generators to seed pancreatic tumour cell lines into microgels of defined size (500 um) and culture them under continuous flow conditions similar to what the cells would experience in the body, giving them a more natural environment in which to develop. We will use AFM to assess the mechanical rigidity of these tumours as cells proliferate and deposit matrix stiffening components into their microenvironment and compare them to the same tumours grown in static wells in order to determine the role and importance of hydraulic cues in microenvironment development. We will then use the platform to investigate the crucial relationship between the mechanical properties of these microtumours and their resistance to the penetration of drugs into their structure. We expect that the stiffer the microtumour, the less drug uptake will be observed. This will then be correlated to microtumour viability for a complete picture of tumour development and resistance to drug delivery. Lastly, using our innovative approach, we will investigate new routes to facilitate drug uptake in solid tumours by exposing microtumours to agents that actively break down the stiff matrix and potentially increase drug penetration. Pancreatic cancer remains one of the deadliest modern-day cancers, with 93% of those being diagnosed dying within 5 years. Current drug treatments for pancreatic cancer are largely ineffective. Only by improving our in vitro models of disease, in which we accurately model the mode of drug resistance, can we improve treatments and patient outcomes. This proposal focussing on pancreatic cancer but will be applicable to all solid tumours.

该提案将使用器官芯片技术和原子力显微镜（AFM）来研究胰腺癌体外培养微肿瘤的机械特性，因为它们在生理相关的流动条件下发展，以及这些肿瘤的机械刚度如何与耐药性相关。实体瘤在体内发展形成致密、坚硬的组织区域，类似于瘢痕组织。在肿瘤内，存在生物物理条件的复杂微环境，其决定疾病的进展并为药物递送提供物理屏障。胰腺癌的特点是致密的纤维性肿瘤块，其中固体应力和液压导致血管塌陷，这是药物输送的主要途径。此外，高的内部压力阻碍药物进入肿瘤块。然而，尽管有这些至关重要的物理因素，大多数药物的体外测试都是针对完全忽略这些生物物理参数的细胞培养模型进行的。该提案将通过使用微流体液滴发生器将胰腺肿瘤细胞系接种到确定尺寸（500 μ m）的微凝胶中，并在类似于细胞在体内经历的连续流动条件下培养它们，从而创造胰腺癌的微肿瘤，为它们提供更自然的发展环境。我们将使用原子力显微镜来评估这些肿瘤的机械刚度细胞增殖和存款矩阵硬化成分到他们的微环境和比较他们的静态威尔斯为了确定液压线索的作用和重要性，在微环境的发展中生长的相同的肿瘤。然后，我们将使用该平台来研究这些微肿瘤的机械特性与它们对药物渗透到其结构中的抵抗力之间的关键关系。我们预计，微肿瘤越硬，观察到的药物摄取越少。然后将其与微肿瘤生存力相关联，以获得肿瘤发展和对药物递送的抗性的完整图像。最后，使用我们的创新方法，我们将研究新的途径，以促进药物吸收的实体瘤暴露于代理，积极打破僵硬的矩阵，并可能增加药物渗透。胰腺癌仍然是最致命的现代癌症之一，93%的人在5年内死亡。目前胰腺癌的药物治疗在很大程度上无效。只有通过改进我们的体外疾病模型，我们才能准确地模拟耐药性模式，才能改善治疗和患者的预后。该提案侧重于胰腺癌，但将适用于所有实体瘤。

项目成果

Free-Standing Hierarchically Porous Silica Nanoparticle Superstructures: Bridging the Nano- to Microscale for Tailorable Delivery of Small and Large Therapeutics

• DOI: 10.1021/acsami.3c16463
• 发表时间: 2024-01-25
• 期刊: ACS APPLIED MATERIALS & INTERFACES
• 影响因子: 9.5
• 作者: Palvai，Sandeep;Kpeglo，Delanyo;Ong，Zhan Yuin
• 通讯作者: Ong，Zhan Yuin

Modelling and breaking down the biophysical barriers to drug delivery in pancreatic cancer

• DOI: 10.1039/d3lc00660c
• 发表时间: 2024-01-19
• 期刊: LAB ON A CHIP
• 影响因子: 6.1
• 作者: Kpeglo，Delanyo;Haddrick，Malcolm;Peyman，Sally A.
• 通讯作者: Peyman，Sally A.