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Sci Rep. 2018 Mar 19;8(1):4797. doi: 10.1038/s41598-018-23140-9.
Many therapeutic agents offer a low useful dose (dose responsible for efficacy)/useless dose (dose eliminated or responsible for toxicity) ratio, mainly due to the fact that therapeutic agents must ensure in one single object all the functions required to deliver the treatment, which leads to compromises in their physico-chemical design. Here we introduce the concept of priming the body to receive the treatment by uncorrelating these functions into two distinct objects sequentially administered: a nanoprimer occupying transiently the main pathway responsible for therapeutic agent limited benefit/risk ratio followed by the therapeutic agent. The concept was evaluated for different nature of therapeutic agents: For nanomedicines we designed a liposomal nanoprimer presenting preferential hepatic accumulation without sign of acute toxicity. This nanoprimer was able to increase the blood bioavailability of nanomedicine correlated with a lower hepatic accumulation. Finally this nanoprimer markedly enhanced anti-tumor efficacy of irinotecan loaded liposomes in the HT-29 tumor model when compared to the nanomedicine alone. Then, for small molecules we demonstrated the ability of a cytochrome inhibitor loaded nanoprimer to increase efficacy of docetaxel treatment. These results shown that specific nanoprimers could be designed for each family of therapeutic agents to answer to their specific needs.
许多治疗药物的有效剂量(产生疗效的剂量)/无效剂量(消除或导致毒性的剂量)比值很低,主要是因为治疗药物必须在一个单一的物体中确保所有用于提供治疗的功能,这导致它们在物理化学设计上存在妥协。在这里,我们引入了通过将这些功能解相关为两个不同的顺序给予的对象来使身体准备好接受治疗的概念:纳米引发剂暂时占据负责治疗药物有限的收益/风险比的主要途径,随后是治疗药物。该概念针对不同性质的治疗药物进行了评估:对于纳米药物,我们设计了一种脂质体纳米引发剂,具有优先的肝脏积累而没有急性毒性的迹象。这种纳米引发剂能够增加与较低的肝脏积累相关的纳米药物的血液生物利用度。最后,与单独的纳米药物相比,该纳米引发剂在 HT-29 肿瘤模型中显著增强了载有伊立替康的脂质体的抗肿瘤疗效。然后,对于小分子,我们证明了载有细胞色素抑制剂的纳米引发剂能够提高多西他赛治疗的疗效。这些结果表明,可以为每种治疗药物家族设计特定的纳米引发剂来满足其特定需求。