期刊
ACS BIOMATERIALS SCIENCE & ENGINEERING
卷 6, 期 9, 页码 4993-5000出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsbiomaterials.0c00485
关键词
dendritic cells; immunotherapy; toll-like receptor; degradable conjugate; coacervate
资金
- Chinese postdoctoral international exchange program
- German Research Foundation (DFG) through the Emmy-Noether program [SFB 1066]
- China Scholarship Council (CSC) [201607650018]
- NIAID [HHSN272201400056C]
- Cornell Startup Grant
- Kom op Tegen Kanker
- Qilu Young Scholar program
- Translational Medicine Core Facility of the Advanced Medical Research Institute, Shandong University
- Pharmaceutical biology sharing platform of Shandong University
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.
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