Peng Wencheng, Yue Yaqi, Zhang Yuting, Li Hao, Zhang Cao, Wang Peiyuan, Cao Yanbing, Liu Xiaolong, Dong Shoulong, Wu Ming, Yao Chenguo
State Key Laboratory of Power Transmission Equipment and System Security and New Technology, Chongqing University, Chongqing 400044, People's Republic of China.
The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People's Republic of China.
APL Bioeng. 2023 Oct 16;7(4):046102. doi: 10.1063/5.0174353. eCollection 2023 Dec.
Precise control of cargo release is essential but still a great challenge for any drug delivery system. Irreversible electroporation (IRE), utilizing short high-voltage pulsed electric fields to destabilize the biological membrane, has been recently approved as a non-thermal technique for tumor ablation without destroying the integrity of adjacent collagenous structures. Due to the electro-permeating membrane ability, IRE might also have great potential to realize the controlled drug release in response to various input IRE parameters, which were tested in a red blood cell (RBC) model in this work. According to the mathematical simulation model of a round biconcave disc-like cell based on RBC shape and dielectric characteristics, the permeability and the pore density of the RBC membrane were found to quantitatively depend on the pulse parameters. To further provide solid experimental evidence, indocyanine green (ICG) and doxorubicin (DOX) were both loaded inside RBCs (RBC@DOX&ICG) and the drug release rates were found to be tailorable by microsecond pulsed electric field (sPEF). In addition, sPEF could effectively modulate the tumor stroma to augment therapy efficacy by increasing micro-vessel density and permeability, softening extracellular matrix, and alleviating tumor hypoxia. Benefiting from these advantages, this IRE-responsive RBC@DOX&ICG achieved a remarkably synergistic anti-cancer effect by the combination of sPEF and chemotherapy in the tumor-bearing mice model, with the survival time increasing above 90 days without tumor burden. Given that IRE is easily adaptable to different plasma membrane-based vehicles for delivering diverse drugs, this approach could offer a general applicability for cancer treatment.
对任何药物递送系统而言，精确控制药物释放至关重要，但仍是一项巨大挑战。不可逆电穿孔（IRE）利用短高压脉冲电场破坏生物膜的稳定性，最近已被批准作为一种非热技术用于肿瘤消融，且不会破坏相邻胶原结构的完整性。由于其电渗透膜的能力，IRE在响应各种输入的IRE参数实现可控药物释放方面可能也具有巨大潜力，本研究在红细胞（RBC）模型中对其进行了测试。根据基于红细胞形状和介电特性的圆形双凹盘状细胞的数学模拟模型，发现红细胞膜的渗透性和孔密度在定量上取决于脉冲参数。为进一步提供确凿的实验证据，将吲哚菁绿（ICG）和阿霉素（DOX）都负载到红细胞内（RBC@DOX&ICG），并发现药物释放速率可通过微秒脉冲电场（sPEF）进行调节。此外，sPEF可通过增加微血管密度和通透性、软化细胞外基质以及缓解肿瘤缺氧来有效调节肿瘤基质，从而增强治疗效果。得益于这些优势，这种IRE响应性的RBC@DOX&ICG在荷瘤小鼠模型中通过sPEF与化疗的联合实现了显著的协同抗癌效果，生存时间延长至90天以上且无肿瘤负荷。鉴于IRE易于应用于不同的基于质膜的载体来递送多种药物，这种方法可能为癌症治疗提供广泛的适用性。
