Department of Biomedical Engineering, University of Minnesota, 7-105 Hasselmo Hall, 312 Church Street S. E., Minneapolis, MN, 55455, USA.
Boston Scientific Corporation, Maple Grove, MN, USA.
Sci Rep. 2021 May 24;11(1):10810. doi: 10.1038/s41598-021-89661-y.
Irreversible electroporation (IRE) is used clinically as a focal therapy to ablate solid tumors. A critical disadvantage of IRE as a monotherapy for cancer is the inability of ablating large tumors, because the electric field strength required is often too high to be safe. Previous reports indicate that cells exposed to certain cationic small molecules and surfactants are more vulnerable to IRE at lower electric field strengths. However, low-molecular-weight IRE sensitizers may suffer from suboptimal bioavailability due to poor stability and a lack of control over spatiotemporal accumulation in the tumor tissue. Here, we show that a synthetic membranolytic polymer, poly(6-aminohexyl methacrylate) (PAHM), synergizes with IRE to achieve enhanced cancer cell killing. The enhanced efficacy of the combination therapy is attributed to PAHM-mediated sensitization of cancer cells to IRE and to the direct cell killing by PAHM through membrane lysis. We further demonstrate sustained release of PAHM from embolic beads over 1 week in physiological medium. Taken together, combining IRE and a synthetic macromolecular sensitizer with intrinsic membranolytic activity and sustained bioavailability may present new therapeutic opportunities for a wide range of solid tumors.
不可逆电穿孔 (IRE) 临床上被用作消融实体肿瘤的一种局部治疗方法。IRE 作为癌症的单一疗法的一个关键缺点是无法消融大肿瘤，因为所需的电场强度通常过高而无法保证安全。以前的报告表明，暴露于某些阳离子小分子和表面活性剂的细胞在较低的电场强度下更容易受到 IRE 的影响。然而，由于低分子重量的 IRE 敏化剂稳定性差且对肿瘤组织中时空积累的控制不足，其生物利用度可能不理想。在这里，我们表明，合成的膜溶胀聚合物聚（6-氨基己基甲基丙烯酸酯）（PAHM）与 IRE 协同作用，以实现增强的癌细胞杀伤。联合治疗的增强疗效归因于 PAHM 通过膜裂解介导癌细胞对 IRE 的敏化以及 PAHM 对癌细胞的直接杀伤。我们进一步证明了在生理介质中，栓塞珠中 PAHM 的持续释放超过 1 周。综上所述，将 IRE 与具有内在膜溶胀活性和持续生物利用度的合成大分子敏化剂相结合，可能为广泛的实体瘤提供新的治疗机会。
