a Department of Neurosurgery , Tohoku University Graduate School of Medicine , Sendai , Miyagi , Japan and.
b Department of Neurological Surgery , University of California San Francisco , San Francisco , California , USA.
Drug Deliv. 2016;23(3):781-6. doi: 10.3109/10717544.2014.914987. Epub 2014 May 28.
In cases of malignant brain tumors, infiltrating tumor cells that exist at the tumor-surrounding brain tissue always escape from cytoreductive surgery and, protected by blood-brain barrier (BBB), survive the adjuvant chemoradiotherapy, eventually leading to tumor recurrence. Local interstitial delivery of chemotherapeutic agents is a promising strategy to target these cells. During our effort to develop effective drug delivery methods by intra-tumoral infusion of chemotherapeutic agents, we found consistent pattern of leakage from the tumor. Here we describe our findings and propose promising strategy to cover the brain tissue surrounding the tumor with therapeutic agents by means of convection-enhanced delivery. First, the intracranial tumor isograft model was used to define patterns of leakage from tumor mass after intra-tumoral infusion of the chemotherapeutic agents. Liposomal doxorubicin, although first distributed inside the tumor, distributed diffusely into the surrounding normal brain once the leakage happen. Trypan blue dye was used to evaluate the distribution pattern of peri-tumoral infusions. When infused intra- or peri-tumorally, infusates distributed robustly into the tumor border. Subsequently, volume of distributions with different infusion scheduling; including intra-tumoral infusion, peri-tumoral infusion after tumor resection, peri-tumoral infusion without tumor removal with or without systemic infusion of steroids, were compared with Evans-blue dye. Peri-tumoral infusion without tumor removal resulted in maximum volume of distribution. Prior use of steroids further increased the volume of distribution. Local interstitial drug delivery targeting tumor surrounding brain tissue before tumor removal should be more effective when targeting the invading cells.
在恶性脑肿瘤的情况下，存在于肿瘤周围脑组织中的浸润性肿瘤细胞总是能够逃避细胞减灭性手术，并在血脑屏障 (BBB) 的保护下，在辅助化疗和放疗后存活下来，最终导致肿瘤复发。局部间质内递药是靶向这些细胞的一种很有前途的策略。在通过向肿瘤内输注化疗药物来开发有效药物递送方法的过程中，我们发现药物从肿瘤中持续泄漏。在这里，我们描述了我们的发现，并提出了一种有前途的策略，通过对流增强递送（convection-enhanced delivery）用治疗剂覆盖肿瘤周围的脑组织。首先，使用颅内肿瘤同种异体移植模型来定义在向肿瘤内输注化疗药物后肿瘤内药物泄漏的模式。多柔比星脂质体虽然首先分布在肿瘤内，但一旦发生泄漏，就会弥散到周围正常脑组织中。台盼蓝染料用于评估周围输注的分布模式。当向肿瘤内或肿瘤周围输注时，输注物会强烈分布到肿瘤边界。随后，比较了不同输注方案的分布体积；包括肿瘤内输注、肿瘤切除后的肿瘤周围输注、肿瘤周围无肿瘤切除的输注以及是否有全身性皮质类固醇输注。肿瘤周围无肿瘤切除的输注导致最大的分布体积。预先使用皮质类固醇进一步增加了分布体积。在肿瘤切除前靶向肿瘤周围脑组织的局部间质药物递送在靶向浸润细胞时应该更有效。
