School of Physics and Astronomy, University of Leeds, Leeds LS2 9JT, United Kingdom; Leeds Institute for Medical Research, Wellcome Trust Brenner Building, St James' University Hospital, Leeds LS9 7TF, United Kingdom.
School of Physics and Astronomy, University of Leeds, Leeds LS2 9JT, United Kingdom.
J Control Release. 2020 Oct 10;326:13-24. doi: 10.1016/j.jconrel.2020.06.011. Epub 2020 Jun 17.
Drug penetration into solid tumours remains a major challenge in the effective treatment of cancer. Microbubble (MB) mediated sonoporation offers a potential solution to this by enhancing the uptake of drugs into cells. Additionally, in using an ultrasound (US) trigger, drug delivery can be localised to the tumour, thus reducing the off-site toxicity associated with systemic delivery. The majority of in vitro studies involving the observation of MB-enhanced drug efficacy have been conducted on 2D monolayer cell cultures, which are known to be poor models for in vivo tumours. 3D spheroid cultures allow for the production of multicellular cultures complete with extracellular matrix (ECM) components. These cultures effectively recreate many of the physiological features of the tumour microenvironment and have been shown to be far superior to previous 2D monolayer models. However, spheroids are typically handled in well-plates in which the fluid environment is static, limiting the physiological relevance of the model. The combination of 3D cultures and microfluidics would allow for the production of a dynamic system in which spheroids are subjected to in vivo like fluid flow and shear stresses. This study presents a microfluidic device containing an array of spheroid traps, into which multiple pre-grown colorectal cancer (CRC) spheroids were loaded. Reservoirs interfaced with the chip use hydrostatic pressure to passively drive flow through the system and subject spheroids to capillary like flow velocities. The use of reservoirs also enabled multiple chips to be run in parallel, allowing for the screening of multiple therapeutic treatments (n = 690 total spheroids analysed). This microfluidic platform was used to investigate MB enhanced drug delivery and showed that co-delivery of 3 μM doxorubicin (DOX) + MB + US reduced spheroid viability to 48 ± 2%, compared to 75 ± 5% observed with 3 μM DOX alone. Delivery of drug loaded MBs (DLMBs), in which DOX-loaded liposomes (DOX-LS) were conjugated to MBs, reduced spheroid viability to 62 ± 3%, a decrease compared to the 75 ± 3% viability observed with DOX-LS in the absence of MBs + US.
药物渗透到实体肿瘤仍然是癌症有效治疗的主要挑战。微泡（MB）介导的声孔作用通过增强细胞对药物的摄取提供了一种潜在的解决方案。此外，使用超声（US）触发可以将药物递送到肿瘤部位，从而降低与全身递送相关的脱靶毒性。大多数涉及观察 MB 增强药物功效的体外研究都是在二维单层细胞培养物上进行的，已知这些培养物是体内肿瘤的不良模型。3D 球体培养物允许生产具有细胞外基质（ECM）成分的多细胞培养物。这些培养物有效地再现了肿瘤微环境的许多生理特征，并且已经被证明比以前的二维单层模型优越得多。然而，球体通常在平板中处理，其中流体环境是静态的，限制了模型的生理相关性。3D 培养物和微流控的结合将允许产生一个动态系统，其中球体受到类似于体内的流体流动和剪切应力。本研究提出了一种包含球体陷阱阵列的微流控装置，其中装载了多个预先生长的结直肠癌（CRC）球体。与芯片接口的储液器利用静水压将流动被动地驱动通过系统，并使球体经受类似于毛细血管的流动速度。储液器的使用还允许多个芯片并行运行，从而允许筛选多种治疗方法（总共分析了 690 个球体）。该微流控平台用于研究 MB 增强药物递送，结果表明，3μM 阿霉素（DOX）+MB+US 共递送将球体活力降低至 48±2%，而单独使用 3μM DOX 观察到的活力为 75±5%。载药微泡（DLMBs）的递送，其中载有阿霉素的脂质体（DOX-LS）与微泡结合，将球体活力降低至 62±3%，与没有 MB+US 时观察到的 75±3%的 DOX-LS 活力相比有所降低。
