Transient Multivalent Nanobody Targeting to CD206-Expressing Cells via PH-Degradable Nanogels

Abstract

To target nanomedicines to specific cells, especially of the immune system, nanobodies can be considered as an attractive tool, as they lack the Fc part as compared to traditional antibodies and, thus, prevent unfavorable Fc-receptor mediated mistargeting. For that purpose, we have site-specifically conjugated CD206/MMR-targeting nanobodies to three types of dye-labeled nanogel derivatives: non-degradable nanogels, acid-degradable nanogels (with ketal crosslinks), and single polymer chains (also obtained after nanogel degradation). All of them can be obtained from the same reactive ester precursor block copolymer. After incubation with naïve or MMR-expressing Chinese hamster ovary (CHO) cells, a nanobody mediated targeting and uptake could be confirmed for the nanobody-modified nanocarriers. Thereby, the intact nanogels that display nanobodies on their surface in a multivalent way showed a much stronger binding and uptake compared to the soluble polymers. Based on their acidic pH-responsive degradation potential, ketal crosslinked nanogels are capable of mediating a transient targeting that gets diminished upon unfolding into single polymer chains after endosomal acidification. Such control over particle integrity and targeting performance can be considered as highly attractive for safe and controllable immunodrug delivery purposes.

Self‐Immolative RAFT‐Polymer End Group Modification

“…[ 66–68 ] In nanomedicine, they furthermore function as targeting moiety for precise delivery of, e.g., pH‐responsive nanogels. [ 69,70 ] One disadvantage compared to antibodies, however, is their weaker pharmacokinetic profile with a relatively short circulation time in the blood stream. [ 71 ]…”

“…[66][67][68] In nanomedicine, they furthermore function as targeting moiety for precise delivery of, e.g., pH-responsive nanogels. [69,70] One disadvantage compared to antibodies, however, is their weaker pharmacokinetic profile with a relatively short circulation time in the blood stream. [71] Conceptually, this might be enhanced by reversible polymer conjugation, e.g., of pDMA as polymer of significantly lower antibody-mediated accelerated blood clearance compared to the widespread PEGylation.…”

Nanobody—A versatile tool for cancer diagnosis and therapeutics

“…The modification of nanobody significantly facilitated the miRNA accumulation in tumor, thus improved miRNA‐mediated antitumor efficacy (Zhang et al, 2020). Furthermore, the nanobody‐targeted pH‐degradable nanogels can mediate a transient targeting, which was considered as a safe and controllable drug delivery system (Scherger et al, 2020).…”

Trendbericht: Makromolekulare Chemie

“…Die responsive Vernetzung erlaubt, Immunzellen allein für das intakte Nanogel transient zu adressieren. 14) Göstl und Herrmann beschäftigten sich mit Polymeren für die Sonopharmakologie beziehungsweise Mechanopharmakologie. 15) Dazu versahen sie Polymere mit mechanochemisch spaltbaren Disulfidbrücken.…”