Mousavi Robab, Soltani Madjid, Souri Mohammad
Department of Mechanical Engineering, K. N. Toosi University of Technology, Tehran, Iran.
Department of Electrical and Computer Engineering, University of Waterloo, Waterloo, Canada.
Drug Deliv Transl Res. 2025 May;15(5):1567-1594. doi: 10.1007/s13346-024-01696-6. Epub 2024 Aug 26.
Primary brain tumors are mostly managed using surgical resection procedures. Nevertheless, in certain cases, a thin layer of tumors may remain outside of the resection process due to the possibility of permanent injury; these residual tumors expose patients to the risk of tumor recurrence. This study has introduced the use of microneedle patches implanted after surgery with a dual-release mechanism for the administration of doxorubicin. The proposed patches possess the capability to administer drugs directly to the residual tumors and initiate chemotherapy immediately following surgical procedures. Three-dimensional simulation of drug delivery to residual tumors in the brain has been performed based on a finite element method. The impact of four important parameters on drug delivery has been investigated, involving the fraction of drug released in the burst phase, the density of microneedles on the patch, the length of microneedles, and the microvascular density of the tumor. The simulation findings indicate that lowering the fraction of drug released in the initial burst phase reduces the maximum average concentration, but the sustained release that continues for a longer period, increasing the bioavailability of free drug. However, the area under curve (AUC) for different release rates remains unchanged due to the fact that an identical dose of drug is supplied in each instance. By increasing the density of microneedles on the patch, concentration accumulation is provided over an extensive region of tumor, which in turn induces more cancer cell death. A comparative analysis of various lengths reveals that longer microneedles facilitate profound penetration into the tumor layers and present better therapeutic response due to extensive area of the tumor which is exposure to chemotherapeutic drugs. Furthermore, high microvascular density, as a characteristic of the tumor microenvironment, is shown to have a significant impact on the blood microvessels drainage of drugs and consequently lower therapeutic response outcome. Our approach offers a computational framework for creating localized drug delivery systems and addressing the challenges related to residual brain tumors.
原发性脑肿瘤大多通过手术切除程序进行治疗。然而，在某些情况下，由于存在永久性损伤的可能性，可能会有一层薄薄的肿瘤残留于切除过程之外；这些残留肿瘤使患者面临肿瘤复发的风险。本研究引入了一种术后植入的微针贴片，其具有双释放机制用于阿霉素给药。所提出的贴片能够将药物直接输送至残留肿瘤，并在手术后立即启动化疗。基于有限元方法对脑部残留肿瘤的药物递送进行了三维模拟。研究了四个重要参数对药物递送的影响，包括突释阶段释放的药物分数、贴片上微针的密度、微针的长度以及肿瘤的微血管密度。模拟结果表明，降低初始突释阶段释放的药物分数会降低最大平均浓度，但持续更长时间的持续释放会增加游离药物的生物利用度。然而，由于每种情况下供应的药物剂量相同，不同释放速率下的曲线下面积（AUC）保持不变。通过增加贴片上微针的密度，可在肿瘤的广泛区域实现浓度积累，进而诱导更多癌细胞死亡。对不同长度的比较分析表明，更长的微针有助于深入穿透肿瘤层，并且由于肿瘤暴露于化疗药物的面积广泛而呈现出更好的治疗反应。此外，作为肿瘤微环境特征的高微血管密度，对药物的血液微血管引流有显著影响，从而降低治疗反应结果。我们的方法为创建局部药物递送系统和解决与残留脑肿瘤相关的挑战提供了一个计算框架。
