Strategies that can reduce the harmful side effects of potent immunomodulatory drugs are in high demand to facilitate clinical translation of the newest generation of immunotherapy. Indeed, uncontrolled triggering of the immune system can lead to life-threatening cascade reactions, such as e.g. cytokine storm. In particular, drug formulations that combine simplicity and degradability are of formidable relevance. Imidazoquinolines are an excellent example of such small molecule immunomodulatory drugs that exhibit in unformulated form a highly undesirable pharmacokinetic profile. Imidazoquinolines are potent inducers of type I interferons that are of great interest in the context of anticancer and antiviral therapy through triggering of Toll like receptors 7 and 8. In this work we aimed to alter the pharmacokinetic profile of imidazoquinolines using a simple, yet efficient, strategy that holds high potential for clinical translation. Hereto, we conjugated an imidazoquinoline to the backbone of poly(aspartate) and further formulated this into a degradable coacervate through complex coacervation with a nontoxic degradable polycation. The intrinsic TLR activity of the imidazoquinoline was well preserved and our formulation strategy offered spatial control over its biological activity in vivo.

中文翻译：

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咪唑并喹啉偶联的可降解凝聚层共轭物用于局部癌症免疫治疗

迫切需要能够降低有效免疫调节药物有害副作用的策略，以促进最新一代免疫疗法的临床翻译。实际上，免疫系统的不受控制的触发可能导致危及生命的级联反应，例如细胞因子风暴。特别地，将简单性和可降解性相结合的药物制剂具有强大的相关性。咪唑并喹啉是这类小分子免疫调节药物的一个很好的例子，它们以未配制的形式表现出非常不希望的药代动力学特征。咪唑并喹啉类是I型干扰素的强效诱导剂，通过触发Toll样受体7和8在抗癌和抗病毒治疗方面引起了人们的极大兴趣。在这项工作中，我们旨在使用简单但有效的策略来改变咪唑并喹啉的药代动力学特征，该策略具有很高的临床翻译潜力。到目前为止，我们将咪唑并喹啉缀合到聚天冬氨酸的骨架上，并通过与无毒可降解聚阳离子的复合凝聚将其进一步配制为可降解凝聚层。咪唑并喹啉的内在TLR活性得到了很好的保留，我们的制剂策略为其体内的生物活性提供了空间控制。