Redox-responsive micellar nanoparticles using benzothiazole-disulfide terminated polymers: employing host–guest complexation for targeted delivery of curcumin†

Abstract

A host–guest interaction-based redox-responsive polymeric nanoparticle system for targeted delivery of curcumin is fabricated. Host–guest interaction between a β-cyclodextrin (β-CD) terminated hydrophilic polymer and curcumin is employed to formulate stable nanosized aggregates. A redox-sensitive disulfide linkage is used to tether the CD moiety onto the polymer chain ends to obtain efficient release inside cancerous cells. For the synthesis of the β-CD terminated redox-responsive polymer, a polyethylene glycol (PEG)-based polymer containing a benzothiazole-disulfide (BDS) group at the chain end was utilized. The BDS-terminated polymers were synthesized using reversible addition–fragmentation chain transfer (RAFT) polymerization by using a BDS-containing chain-transfer agent (CTA). Initially, the post-polymerization modification abilities of these polymers were demonstrated by successful conjugation of model thiol functional compounds such as furfuryl thiol and Bodipy-SH, a fluorescent hydrophobic dye. To prepare a nanoaggregate forming polymer precursor, a thiol functional β-CD host moiety was conjugated to the BDS end groups of the reactive polymer through redox-responsive disulfide linkage formation. The other end of the β-CD-containing polymer was capped with an integrin-targeting cyclic peptide (cRGDfK). While no aggregates were observed in the aqueous medium for the BDS-containing parent polymer, the β-CD attached polymers gave nanosized aggregates with average sizes below 150 nm. Curcumin-loaded nanoaggregates were obtained through the inclusion complexation of curcumin molecules with β-CD moieties. It was shown that enhanced drug release occurred upon exposure of the nanoaggregates to the glutathione (GSH) environment. While the parent BDS functional polymers and β-CD-containing polymeric aggregates were non-toxic to healthy fibroblast cells, curcumin-loaded aggregates showed dose-dependent toxicity against the U-87 glioblastoma cancer cell line. The peptide-targeting group containing nanoparticles showed slightly higher toxicity and enhanced cellular internalization. The modular nanoparticle system disclosed here could be employed to address challenges in the delivery of hydrophobic drugs to cancer cells.