Department of Biomedical Engineering, University of Virginia, Box 800759, Charlottesville, VA, 22908, USA.
Department of Pharmacology, University of Virginia, Charlottesville, VA, 22908, USA.
Drug Deliv Transl Res. 2023 Dec;13(12):3145-3153. doi: 10.1007/s13346-023-01377-w. Epub 2023 Jun 19.
Sparse scan partial thermal ablation (TA) with focused ultrasound (FUS) may be deployed to treat solid tumors and increase delivery of systemically administered therapeutics. Furthermore, C6-ceramide-loaded nanoliposomes (CNLs), which rely upon the enhanced-permeation and retention (EPR) effect for delivery, have shown promise for treating solid tumors and are being tested in clinical trials. Here, our objective was to determine whether CNLs synergize with TA in the control of 4T1 breast tumors. CNL monotherapy of 4T1 tumors yielded significant intratumoral bioactive C6 accumulation by the EPR effect, but tumor growth was not controlled. TA increased bioactive C6 accumulation by ~ 12.5-fold over the EPR effect. In addition, TA + CNL caused shifts in long-chain to very-long-chain ceramide ratios (i.e., C16/24 and C18/C24) that could potentially contribute to tumor control. Nonetheless, these changes in intratumoral ceramide levels were still insufficient to confer tumor growth control beyond that achieved when combining with TA with control "ghost" nanoliposomes (GNL). While this lack of synergy could be due to increased "pro-tumor" sphingosine-1-phosphate (S1P) levels, this is unlikely because S1P levels exhibited only a moderate and statistically insignificant increase with TA + CNL. In vitro studies showed that 4T1 cells are highly resistant to C6, offering the most likely explanation for the inability of TA to synergize with CNL. Thus, while our results show that sparse scan TA is a powerful approach for markedly enhancing CNL delivery and generating "anti-tumor" shifts in long-chain to very-long-chain ceramide ratios, resistance of the tumor to C6 can still be a rate-limiting factor for some solid tumor types.
稀疏扫描部分热消融（TA）联合聚焦超声（FUS）可用于治疗实体瘤并增加系统给予治疗药物的递送。此外，依赖增强渗透和保留（EPR）效应递送至肿瘤部位的神经酰胺负载的纳米脂质体（CNL），在治疗实体瘤方面显示出巨大的潜力，并正在临床试验中进行测试。在此，我们的目标是确定 CNL 是否与 TA 联合控制 4T1 乳腺癌肿瘤。CNL 单药治疗 4T1 肿瘤通过 EPR 效应使肿瘤内生物活性 C6 积累显著增加，但肿瘤生长未得到控制。TA 使生物活性 C6 的积累增加了约 12.5 倍，超过了 EPR 效应。此外，TA+CNL 导致长链至超长链神经酰胺比率（即 C16/24 和 C18/C24）发生变化，这可能有助于肿瘤控制。尽管如此，这些肿瘤内神经酰胺水平的变化仍然不足以在与 TA 联合使用时提供比与对照“幽灵”纳米脂质体（GNL）联合使用时更好的肿瘤生长控制。虽然这种缺乏协同作用可能是由于增加的“促肿瘤”鞘氨醇-1-磷酸（S1P）水平所致，但这不太可能，因为 S1P 水平仅适度增加且统计学上不显著与 TA+CNL 相关。体外研究表明，4T1 细胞对 C6 具有高度抗性，这最有可能解释了 TA 无法与 CNL 协同作用的原因。因此，虽然我们的结果表明稀疏扫描 TA 是一种强大的方法，可显著增强 CNL 的递送并产生长链至超长链神经酰胺比率的“抗肿瘤”变化，但肿瘤对 C6 的抗性仍然是某些实体瘤类型的限速因素。
