具有双药释放能力的微针贴片用于脑肿瘤药物递送

原发性脑肿瘤主要采用手术切除治疗。然而，在某些情况下，由于可能导致永久性损伤，肿瘤的薄层部分可能在切除过程中未能完全切除，这些残留肿瘤使患者面临肿瘤复发的风险。本研究引入了手术后植入的微针贴片，具备双重释放机制，用于多柔菌素的给药。所提出的贴片能够直接向残留肿瘤施药，并在手术后立即启动化疗。基于有限元方法进行了脑内残留肿瘤药物递送的三维数值模拟。研究了四个重要参数对药物递送的影响，包括爆发期药物释放比例、微针密度、微针长度以及肿瘤的微血管密度。模拟结果表明，降低初始爆发期的药物释放比例可降低最大平均浓度，但持续时间更长的缓释能增强游离药物的生物利用度。然而，不同释放速率的曲线下面积（AUC）保持不变，因为每次供应的药物剂量相同。增加微针密度可在肿瘤的广泛区域内实现浓度积累，从而诱导更多癌细胞死亡。对不同长度的比较显示，较长的微针能更深入穿透肿瘤层，因暴露面积更大，具有更好的治疗效果。此外，肿瘤微环境的特征——高微血管密度，对药物通过血微血管的排出具有显著影响，进而降低治疗效果。我们的方法提供了一个计算模拟框架，用于创建局部药物递送系统，并应对残留脑肿瘤的挑战。

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.