Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan.
Department of Microbiology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
Acta Biomater. 2021 May;126:372-383. doi: 10.1016/j.actbio.2021.03.044. Epub 2021 Mar 24.
Intralipid, a clinically used lipid emulsion, was reportedly utilized as one strategy to suppress off-target delivery of anticancer nanomedicines; Intralipid also effectively improved drug delivery to tumors and produced better therapeutic effects. However, the mechanisms involved-the why and how-in Intralipid's facilitation of delivery of nanomedicines to tumors have not yet been reported in detail. In this study, we investigated Intralipid and discovered the beneficial effects of Intralipid pretreatment when using three anticancer nanomedicines, including the clinically approved drug doxorubicin (Doxil). Intralipid pretreatment induced a 40% reduction in liver uptake of a polymeric nanoprobe used in photodynamic therapy as well as a 1.5-fold-increased nanomedicine accumulation in tumors. This increased accumulation consequently led to significantly better therapeutic effects, and this finding was validated by using Doxil. As an interesting result, Intralipid pretreatment significantly prolonged the plasma half-life of nanomedicines in normal healthy mice but not in tumor-bearing mice, which suggests that tumors become an alternative route of nanomedicine delivery when liver delivery is suppressed. Also, we found markedly increased tumor blood flow, as measured by fluorescence angiography, and significantly lower blood viscosity after Intralipid pretreatment. All our results together indicate that Intralipid treatment not only suppressed off-target nanomedicine delivery by the reticuloendothelial system, but more important, it enhanced nanomedicine delivery to tumors by improving tumor blood flow, which is key to satisfactory drug delivery via the enhanced permeability and retention effect. Significantly better therapeutic outcomes were thus achieved by the strategy of combining utilization of nanomedicines and Intralipid pretreatment. STATEMENT OF SIGNIFICANCE: Off-target delivery to organs such as the liver and obstructed tumor blood flow as is often seen in advanced cancers are major barriers to the therapeutic efficacy of anticancer nanomedicines. Intralipid has been shown effective for suppressing nanomedicine accumulation in the liver, resulting in improved anticancer effects. Unraveling the mechanisms involved in this process will be greatly helpful for the clinical application of anticancer nanomedicines. We reported here that Intralipid could also significantly increase tumor delivery of nanomedicine, which is beneficial for improving tumor blood flow and lowering blood viscosity. To our knowledge, this is the first study to investigate the role of Intralipid in this regard. This knowledge provides a solid rationale for the use of Intralipid in combination with anticancer nanomedicines.
Intralipid 是一种临床应用的脂质乳剂，据报道可作为抑制抗癌纳米药物脱靶递送的策略之一；Intralipid 还能有效提高药物向肿瘤的递送，并产生更好的治疗效果。然而，Intralipid 促进纳米药物递送到肿瘤的相关机制——原因和方式——尚未详细报道。在这项研究中，我们研究了 Intralipid，并发现 Intralipid 预处理对三种抗癌纳米药物（包括临床批准的药物阿霉素（Doxil））的有益效果。Intralipid 预处理可使用于光动力治疗的聚合物纳米探针的肝脏摄取减少 40%，并使肿瘤中纳米药物的积累增加 1.5 倍。这种增加的积累导致了显著更好的治疗效果，这一发现通过使用 Doxil 得到了验证。作为一个有趣的结果，Intralipid 预处理可显著延长正常健康小鼠中纳米药物的血浆半衰期，但不能延长肿瘤小鼠中的纳米药物半衰期，这表明当抑制肝脏递送时，肿瘤成为纳米药物递送的替代途径。此外，我们发现荧光血管造影术测量的肿瘤血流量明显增加，Intralipid 预处理后血液粘度明显降低。我们所有的结果共同表明，Intralipid 治疗不仅通过网状内皮系统抑制了纳米药物的脱靶递送，而且更重要的是，它通过改善肿瘤血流增强了纳米药物向肿瘤的递送，这是通过增强渗透性和保留效应实现令人满意的药物递送的关键。通过结合利用纳米药物和 Intralipid 预处理的策略，从而实现了更好的治疗效果。
纳米药物向肝脏等器官的脱靶递送以及晚期癌症中经常出现的肿瘤血流阻塞是抗癌纳米药物治疗效果的主要障碍。Intralipid 已被证明可有效抑制纳米药物在肝脏中的积累，从而提高抗癌效果。阐明这一过程涉及的机制将极大地有助于抗癌纳米药物的临床应用。我们在这里报告，Intralipid 还可以显著增加纳米药物向肿瘤的递送，这有利于改善肿瘤血流并降低血液粘度。据我们所知，这是第一项研究 Intralipid 在这方面作用的研究。这一知识为将 Intralipid 与抗癌纳米药物联合使用提供了坚实的理由。
