Cationic solid lipid nanoparticles (cSLNs) are promising nanoparticles for controlled drug delivery. Increasing surface charge and/or reducing PEG density enhance cellular uptake of cSLNs in vitro, but for unknown reasons fail to improve drug delivery in vivo. Herein, we show that cSLNs present a risk for systemic platelet activation and aggregation in vivo, and this toxic effect can be significantly augmented by increasing the surface charge and reducing the PEG density. Furthermore, thrombotic toxicity significantly reduces blood circulation time and in vivo cellular uptake of cSLNs. Mechanistic studies revealed that the intrinsic coagulation pathway is responsible for cSLN-induced platelet activation. Importantly, pretreatment of the recipient mice with heparin, a clinically-approved intrinsic coagulation inhibitor, was highly effective in preventing toxicity, prolonging the circulation time of cSLNs, and improving cSLN-based antitumor drug delivery and therapeutic efficacy in tumor-bearing mice. This study offers a useful strategy for improving both the safety and efficacy of cSLN-based anticancer therapies.

阳离子固体脂质纳米颗粒（cSLN）是用于控制药物输送的有前途的纳米颗粒。增加表面电荷和/或降低PEG密度可以增强cSLNs在体外的细胞吸收，但由于不明原因无法改善体内药物的输送。在这里，我们表明cSLNs存在体内全身血小板活化和聚集的风险，并且可以通过增加表面电荷和降低PEG密度来显着增强这种毒性作用。此外，血栓毒性极大地减少了血液循环时间和体内细胞对cSLN的摄取。机理研究表明，内在的凝血途径是cSLN诱导的血小板活化的原因。重要的是，用肝素（一种临床批准的内在凝血抑制剂）对受体小鼠进行预处理在预防毒性，延长cSLNs的循环时间以及改善基于cSLN的抗肿瘤药物的递送以及对荷瘤小鼠的治疗效果方面非常有效。这项研究为提高基于cSLN的抗癌疗法的安全性和有效性提供了有用的策略。