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

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.

Systemic Immunotherapy with Micellar Resiquimod–Polymer Conjugates Triggers a Robust Antitumor Response in a Breast Cancer Model

“…[34] The formulation of immunomodulating nanocarriers can be via physical encapsulation of the immunomodulator(s) into NPs, through covalent attachment onto preformed NPs, or covalent attachment to surfactant-like molecules/polymers which are then transformed into NPs. [14,21,[35][36][37][38][39] Taking into account the need to retain the immunomodulating activity of the cargo, the encapsulation approach is advantageous in that there is no structural alteration; thus, activity is typically not impacted. However, the encapsulation of some immunomodulating molecules (e.g., water soluble imidazoquinolines) can be quite challenging, leading to poor loading efficiencies, and moreover, the possibility of cargo leakage from the carrier.…”

“…[ 34 ] The formulation of immunomodulating nanocarriers can be via physical encapsulation of the immunomodulator(s) into NPs, through covalent attachment onto preformed NPs, or covalent attachment to surfactant‐like molecules/polymers which are then transformed into NPs. [ 14,21,35–39 ]…”

Targeted Repolarization of Tumor‐Associated Macrophages via Imidazoquinoline‐Linked Nanobodies

“…[39] For this study, we chose 1-(4-(aminomethyl)benzyl)-2-butyl-1H-imidazo [4,5c]quinolin-4-amine (IMDQ) as a highly potent IMQ variant with a primary amine [33,40,41] that enables chemical conjugation to macromolecules. [36,[42][43][44] IMDQ could be synthesized following previously reported protocols [45] with some minor adjustments, as documented in the Supporting Information.…”

Trendbericht: Makromolekulare Chemie

“…Zusätzlich lassen sich immunstimulierende TLR7/8-Agonisten binden, die nur als Nanogel funktionell aktiv sind. 13) Ein ähnliches Nanogelsystem mit Einzelkettenfragment-Antikörpern aus dem Lama ermöglicht rezeptorspezifisches Targeting von Immunzellen. Die responsive Vernetzung erlaubt, Immunzellen allein für das intakte Nanogel transient zu adressieren.…”