Enzyme and PH Dual Responsive Linear-dendritic Block Copolymer Micelles Based on a Phenylalanyl-lysine Motif and Peripherally Ketal-functionalized Dendron As Potential Drug Carriers

Stimuli-responsive linear-dendritic block copolymers (LDBCs) have attracted significant research attention as novel drug carriers. We report here three generations of new enzyme and pH dual responsive linear-dendritic block copolymers (LDBCs) with a phenylalanyl-lysine (Phe-Lys) dipeptide linking hydrophilic linear poly(-vinylpyrrolidone) (PNVP) and a hydrophobic peripherally ketal-functionalized dendron derived from 2,2'-bis(hydroxymethyl)propionic acid (bis-MPA). The LDBCs are synthesized a combination of interchange of xanthates/reversible addition-fragmentation chain transfer (MADIX/RAFT) polymerization of -vinylpyrrolidone (NVP) and "chain-first" strategy. Their structures are confirmed by H NMR spectra. The gel permeation chromatograph (GPC) analysis revealed that the LDBCs have a narrow molecular weight distribution (PDI ≤ 1.25). The amphiphilic LDBCs can self-assemble into spherical nanomicelles in aqueous solution. The presence of enzyme or/and the change of pH cause disassembly of micelles to release encapsulated cargos. The release rates of the guest molecules are faster in buffer solution at pH 5.0 than those upon the addition of the activating enzyme and can be fine-tuned by changing the generation of bis-MPA dendrons. The combination of enzyme and pH dual stimuli results in significantly accelerated and more complete release of the loaded hydrophobic guests. The cell viability assay confirmed the favorable biocompatibility until the LDBC micelle concentration reached 800 μg mL. These results indicate that the LDBCs can be considered as a good candidate for targeting drug delivery.