Local and long-lasting administration of potent chemotherapeutics is a promising therapeutic intervention to increase the efficiency of chemotherapy of hard-to-treat tumors such as the most lethal brain tumors, glioblastomas (GBM). However, despite high toxicity for GBM cells, potent chemotherapeutics such as gemcitabine (Gem) cannot be widely implemented as they do not efficiently cross the blood brain barrier (BBB). As an alternative method for continuous administration of Gem, we here operate freestanding iontronic pumps – “GemIPs” – equipped with a custom-synthesized ion exchange membrane (IEM) to treat a GBM tumor in an avian embryonic system. We compare GemIP treatment effects with a topical metronomic treatment and observe that a remarkable growth inhibition was only achieved with steady dosing GemIPs. Daily topical drug administration (at the maximum dosage that was not lethal for the embryonic host organism) did not decrease tumor sizes, while both treatment regimes caused S-phase cell cycle arrest and apoptosis. We hypothesize that the pharmacodynamic effects generate different intratumoral drug concentration profiles for each technique, which causes this difference in outcome. We created a digital model of the experiment, which proposes a fast decay in the local drug concentration for the topical daily treatment, but a long-lasting high local concentration of Gem close to the tumor area with GemIPs. Continuous chemotherapy with iontronic devices opens new possibilities in cancer treatment: the long-lasting and highly local dosing of clinically available, potent chemotherapeutics to greatly enhance treatment efficiency without systemic side-effects. Iontronic pumps (GemIPs) provide continuous and localized administration of the chemotherapeutic gemcitabine (Gem) for treating glioblastoma . By generating high and constant drug concentrations near the vascularized growing tumor, GemIPs offer an efficient and less harmful alternative to systemic administration. Continuous GemIP dosing resulted in remarkable growth inhibition, superior to daily topical Gem application at higher doses. Our digital modelling shows the advantages of iontronic chemotherapy in overcoming limitations of burst release and transient concentration profiles, and providing precise control over dosing profiles and local distribution. This technology holds promise for future implants, could revolutionize treatment strategies, and offers a new platform for studying the influence of timing and dosing dependencies of already-established drugs in the fight against hard-to-treat tumors.

中文翻译：

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连续离子化学疗法可减少禽类胚胎体内模型中的脑肿瘤生长


局部和持久施用强效化疗药物是一种有前途的治疗干预措施，可提高难以治疗的肿瘤（例如最致命的脑肿瘤胶质母细胞瘤（GBM））的化疗效率。然而，尽管吉西他滨 (Gem) 等强效化疗药物对 GBM 细胞具有高毒性，但由于无法有效穿过血脑屏障 (BBB)，因此无法广泛应用。作为持续施用 Gem 的替代方法，我们使用配备定制合成离子交换膜 (IEM) 的独立式离子泵（“GemIPs”）来治疗禽类胚胎系统中的 GBM 肿瘤。我们将 GemIP 治疗效果与局部节律治疗效果进行比较，并观察到只有稳定剂量的 GemIP 才能实现显着的生长抑制。每日局部给药（对胚胎宿主生物体不致死的最大剂量）不会减小肿瘤大小，而两种治疗方案都会导致 S 期细胞周期停滞和细胞凋亡。我们假设每种技术的药效效应都会产生不同的瘤内药物浓度分布，从而导致结果的差异。我们创建了该实验的数字模型，该模型提出局部日常治疗的局部药物浓度会快速衰减，但使用 GemIPs 会在靠近肿瘤区域的地方长期保持高局部浓度。使用离子电子设备的连续化疗为癌症治疗开辟了新的可能性：临床上可用的强效化疗药物的持久和高度局部给药，可大大提高治疗效率，而不会产生全身副作用。 离子泵 (GemIP) 提供化疗药物吉西他滨 (Gem) 的连续和局部给药，用于治疗胶质母细胞瘤。通过在血管化生长的肿瘤附近产生高且恒定的药物浓度，GemIP 为全身给药提供了一种高效且危害较小的替代方案。连续使用 GemIP 会产生显着的生长抑制作用，优于每天局部使用较高剂量的 Gem。我们的数字模型显示了离子化学疗法在克服突发释放和瞬时浓度曲线的局限性以及提供对剂量曲线和局部分布的精确控制方面的优势。这项技术为未来的植入带来了希望，可以彻底改变治疗策略，并为研究现有药物在对抗难以治疗的肿瘤中的时间和剂量依赖性的影响提供了一个新平台。