Control over imidazoquinoline immune stimulation by pH-degradable poly(norbornene) nanogels

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

Assembly of pH-Responsive Antibody-Inspired Protein-Drug Conjugates

With the advent of chemical strategies that allow the design of smart bioconjugates, peptide- and protein-drug conjugates are emerging as highly efficient therapeutics to overcome limitations of conventional treatment, as exemplified by antibody-drug conjugates. While targeting peptides serve similar roles as antibodies to recognize overexpressed receptors on diseased cell surfaces, peptide-drug conjugates suffer from poor stability and bioavailability due to their low molecular weights. Through a combination of a supramolecular protein-based assembly platform and a pH-responsive dynamic covalent linker, we devise herein the convenient assembly of a trivalent protein-drug conjugate. The conjugate mimics key features of antibody-drug conjugates such as (1) a multipartite structure, (2) peptide recognition sites arranged at distinct locations and at defined distances, (3) a high molecular weight protein scaffold, and (4) an attached drug molecule. These antibody-inspired protein-drug conjugates target cancer cells that overexpress somatostatin receptors, enable controlled release in the microenvironment of cancer cells through an entirely new dynamic covalent biotin linker and exhibit stability in biological media