The targeted local delivery of anticancer therapeutics offers an alternative to systemic chemotherapy for oral cancers not amenable to surgical excision. However, epithelial barrier function can pose a challenge to their passive topical delivery. The charged, deformable liposomes—“iontosomes”—described here are able to overcome the buccal mucosal barrier via a combination of the electrical potential gradient imposed by iontophoresis and their shape-deforming characteristics. Two chemotherapeutic agents with very different physicochemical properties, cisplatin (CDDP) and docetaxel (DTX), were co-encapsulated in cationic iontosomes comprising 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and Lipoid-S75. The entrapment of CDDP was improved by formulating it in anionic reverse micelles of dipalmitoyl-sn-glycero-3-phospho-rac-glycerol sodium (DPPG) prior to loading in the iontosomes. Cryo-TEM imaging clearly demonstrated the iontosomes’ electroresponsive shape-deformable properties. The in vitro transport study using porcine mucosa indicated that iontosomes did not enter the mucosa without an external driving force. However, anodal iontophoresis resulted in significant amounts of co-encapsulated CDDP and DTX being deposited in the buccal mucosa; e.g., after current application for 10 min, the deposition of CDDP and DTX was 13.54 ± 1.78 and 10.75 ± 1.75 μg/cm² cf. 0.20 ± 0.07 and 0.19 ± 0.09 μg/cm² for the passive controls—i.e., 67.7- and 56.6-fold increases—without any noticeable increase in their transmucosal permeation. Confocal microscopy confirmed that the iontosomes penetrated the mucosa through the intercellular spaces and that the penetration depth could be controlled by varying the duration of current application. Overall, the results suggest that the combination of topical iontophoresis with a suitable nanocarrier system can be used to deliver multiple “physicochemically incompatible” chemotherapeutics selectively to oral cancers while decreasing the extent of systemic absorption and the associated risk of side effects.

中文翻译：

---

离子小体：用于局部离子电渗疗法将化学治疗剂局部输送至颊粘膜的电反应性脂质体。

针对不适合手术切除的口腔癌，靶向抗癌治疗剂的局部递送为全身化疗提供了替代方法。然而，上皮屏障功能可能对其被动局部递送构成挑战。此处介绍的带电可变形脂质体（“离子体”）能够通过离子电渗疗法施加​​的电势梯度及其形状变形特性的组合来克服颊黏膜屏障。将两种具有非常不同的理化性质的化学治疗剂顺铂（CDDP）和多西他赛（DTX）共包裹在包含1,2-二油酰基-3-三甲基铵丙烷（DOTAP）和脂质类S75的阳离子离子体中。在装入离子体之前，将其配制成二棕榈酰-sn-甘油-3-磷酸-rac-甘油钠（DPPG）的阴离子反胶束，可改善CDDP的包封性。低温TEM成像清楚地证明了离子体的电响应形状可变形特性。使用猪粘膜的体外转运研究表明，如果没有外部驱动力，离子体就不会进入粘膜。但是，阳极离子电渗疗法导致大量共包封的CDDP和DTX沉积在颊粘膜中。例如，在通电10分钟后，CDDP和DTX的沉积分别为13.54±1.78和10.75±1.75μg/ cm 使用猪粘膜的体外转运研究表明，如果没有外部驱动力，离子体就不会进入粘膜。但是，阳极离子电渗疗法导致大量共包封的CDDP和DTX沉积在颊粘膜中。例如，在通电10分钟后，CDDP和DTX的沉积分别为13.54±1.78和10.75±1.75μg/ cm 使用猪粘膜的体外转运研究表明，如果没有外部驱动力，离子体就不会进入粘膜。但是，阳极离子电渗疗法导致大量共包封的CDDP和DTX沉积在颊粘膜中。例如，在通电10分钟后，CDDP和DTX的沉积分别为13.54±1.78和10.75±1.75μg/ cm²比照 被动对照的0.20±0.07和0.19±0.09μg/ cm ²，即增加67.7和56.6倍，而其透粘膜渗透性却没有任何明显的增加。共聚焦显微镜证实离子体通过细胞间间隙穿透粘膜，并且可以通过改变当前应用的持续时间来控制穿透深度。总体而言，结果表明局部离子电渗疗法与合适的纳米载体系统的组合可用于选择性地向口腔癌提供多种“理化不相容”化学疗法，同时降低全身吸收的程度和相关的副作用风险。