Controlling the function of bioactive worm micelles by enzyme-cleavable non-covalent inter-assembly cross-linking

• Published in: Journal of controlled release Vol. 368; pp. 15 - 23
• Main Authors: Romanovska, Alina, Schmidt, Martin, Brandt, Volker, Tophoven, Jonas, Tiller, Joerg C.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2024
• Subjects: Ciprofloxacin; Cross-linked micelles; Lipase-induced release; Poly(2-oxazoline); Polymer antibtiotic conjugate; Lipase-induced release; Poly(2-oxazoline); Ciprofloxacin; Cross-linked micelles; Polymer antibtiotic conjugate
• DOI: 10.1016/j.jconrel.2024.02.013
• ISSN: 0168-3659

Drugs that form self-assembled supramolecular structures to be most-active is a promising way of creating new highly specific and active pharmaceuticals. Controlling the activity of bioactive supramolecular structures such as drug-loaded micelles is possible by both core/shell and inter-assembly cross-linking. However, if the flexibility of the assembly is mandatory for the activity cross-linking is not feasible. Thus, such structures cannot be manipulated in their activity. The present study demonstrates a novel concept to control the activity of not drug-releasing, non-cross-linked bioactive superstructures. This is achieved by formation of nanostructured nanoparticles derived by non-covalent inter-assembly cross-linking of the superstructures. This is shown on the example of amphiphilic diblock-copolymers conjugated with the antibiotic ciprofloxacin (CIP). These polymer-antibiotic conjugates form worm micelles, which greatly activate the conjugated antibiotic without releasing it. Non-covalent inter-assembly cross-linking of these CIP-worm-micelles with amphiphilic triblock copolymers terminated with lipase-cleavable esters leads to nanostructured nanoparticles that resemble cross-linked worm micelles and show an up to 135-fold lower activity than the free worm micelles. The activity of the worm-micelles can be fully recovered by cleaving the end groups of the polymeric cross-linker with lipase. [Display omitted] •nanoprecipitation inactivates ciprofloxacin polymer conjugate (PAC) worm micelles.•non-covalent cross-linking of PAC by triblockcopolymers (TBC) with ester end groups.•lipase cleaves ester end groups of TBC in aggregates.•lipase destroys superstructure of aggregates.•lipase releases activated, antibacterial PAC worm micelles.