posted on 2020-08-11, 15:16authored byHui Li, Simon Van Herck, Yongjun Liu, Yanyun Hao, Xiaochu Ding, Lutz Nuhn, Zifu Zhong, Francis Combes, Niek N. Sanders, Stefan Lienenklaus, Stefaan D. Koker, Sunil A. David, Yadong Wang, Bruno G. De Geest, Zhiyue Zhang
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.