Control over Imidazoquinoline Immune Stimulation by pH-Degradable Poly(norbornene) Nanogels.

Johannes Kockelmann,Lutz Nuhn,Michaela Pieszka,Judith Stickdorn,Sunil A David,Bruno G De Geest,Jana De Vrieze,Sabah Kasmi,David Yuen W Ng

doi:10.1021/acs.biomac.0c00205

Johannes Kockelmann, Lutz Nuhn + Show 7 more

Open Access

https://doi.org/10.1021/acs.biomac.0c00205

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Abstract

The reactivation of the innate immune system by toll-like receptor (TLR) agonists holds promise for anticancer immunotherapy. Severe side effects caused by unspecific and systemic activation of the immune system upon intravenous injection prevent the use of small-molecule TLR agonists for such purposes. However, a covalent attachment of small-molecule imidazoquinoline (IMDQ) TLR7/8 agonists to pH-degradable polymeric nanogels could be shown to drastically reduce the systemic inflammation but retain the activity to tumoral tissues and their draining lymph nodes. Here, we introduce the synthesis of poly(norbornene)-based, acid-degradable nanogels for the covalent ligation of IMDQs. While the intact nanogels trigger sufficient TLR7/8 receptor stimulation, their degraded version of soluble, IMDQ-conjugated poly(norbornene) chains hardly activates TLR7/8. This renders their clinical safety profile, as degradation products are obtained, which would not only circumvent nanoparticle accumulation in the body but also provide nonactive, polymer-bound IMDQ species. Their immunologically silent behavior guarantees both spatial and temporal control over immune activity and, thus, holds promise for improved clinical applications.

Highlights

The maturation of dendritic cells (DCs) to antigen-presenting cells, the subsequent development of a T-cell-dependent immune reaction, and the secretion of various chemokines are of key interest in cancer immunotherapy.[1]
We previously reported on immune stimulatory nanogels, based on reactive amphiphilic poly(methacrylamide) block copolymers derived from mPEG- and pentafluorophenyl esterbearing acrylates, that can be prepared by RAFT polymerization and subsequent versatile postpolymerization modification.[22]
We investigated other polymerization techniques and monomer systems and thereby observed that, in analogy to our previously reported studies, the ring-opening metathesis polymerization (ROMP) of norbornenes with mPEG or pentafluorophenyl ester side chains can provide rapid access to highly modifiable, pH-degradable nanogels

Summary

Introduction

The maturation of dendritic cells (DCs) to antigen-presenting cells, the subsequent development of a T-cell-dependent immune reaction, and the secretion of various chemokines are of key interest in cancer immunotherapy.[1]. A strategy to increase the DC maturation and antigen presentation to T-cells includes the activation of toll-like receptors (TLR).[6] These receptors normally recognize pathogen-associated molecular patterns (PAMPs) like lipopolysaccharides, double- or single-stranded RNA, etc. Their activation leads to the differentiation of immature DCs and the stimulation of an active immune response.[7] Among others, potent TLR agonists like the TLR-7/8 agonist imidazoquinoline (IMDQ) are under investigation as adjuvants in vaccination[8] as well as for their use in anticancer immunotherapy.[9]

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