Micellar Paclitaxel-Initiated RAFT Polymer Conjugates with Acid-Sensitive Behavior

Benoit Louage; Mies J van Steenbergen; Lutz Nuhn; Martijn D P Risseeuw; Izet Karalic; Johan Winne; Serge Van Calenbergh; Wim E Hennink; Bruno G De Geest

doi:10.1021/acsmacrolett.6b00977

Micellar Paclitaxel-Initiated RAFT Polymer Conjugates with Acid-Sensitive Behavior

ACS Macro Lett. 2017 Mar 21;6(3):272-276. doi: 10.1021/acsmacrolett.6b00977. Epub 2017 Mar 3.

Authors

Benoit Louage¹, Mies J van Steenbergen², Lutz Nuhn¹, Martijn D P Risseeuw³, Izet Karalic³, Johan Winne⁴, Serge Van Calenbergh³, Wim E Hennink², Bruno G De Geest¹

Affiliations

¹ Laboratory of Pharmaceutical Technology, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
² Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584CG Utrecht, The Netherlands.
³ Laboratory for Medicinal Chemistry, Department of Pharmaceutics, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
⁴ Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 S4, 9000 Ghent, Belgium.

PMID: 35650901
DOI: 10.1021/acsmacrolett.6b00977

Abstract

Acid-sensitive paclitaxel (PTX)-polymer conjugates were designed by applying a grafting-from-drug RAFT approach. PTX was linked through either a cyclic or a linear, acid-sensitive acetal moiety. Relative to direct esterification of PTX, which occurred regioselectively at the C₂' OH-group, direct acetalization was observed at either the C₂' or the C₇ OH-group of PTX. This yielded two regioisomers of acetal-based PTX-functionalized RAFT chain transfer agents (CTAs). Subsequent polymerization with N,N-dimethylacrylamide (DMA) resulted in amphiphilic highly defined, acetal-based PTX-polymer conjugates with nearly identical features in terms of polymer definition and micellar self-assembly behavior, but with distinct PTX release kinetics and absence of burst release. This was further reflected by their in vitro biological performance, giving insights into the difference of the release mechanism between ester- and acetal-based PTX-polymer conjugates.