Cathepsin B and thermal dual-stimuli responsive linear-dendritic block copolymer micelles for anticancer drug delivery

In this study, two linear poly(N-vinylcaprolactam)s (PNVCLs) with different molecular weights were first synthesized as polymeric supporters by reversible addition-fragmentation chain transfer polymerization and then were used to prepare cathepsin B and thermal dual-stimuli responsive amphiphilic linear-dendritic block copolymers (LDBCs) PNVCLn-b-d(Phe-Lys)(1-3) (n = 66, 100) with linear PNVCL and dendritic phenylalanyl-lysine (Phe-Lys) dipeptides via stepwise peptide chemistry. The copolymers were characterized by H-1 NMR spectra and gel permeation chromatography and exhibited a controlled molecular weight and a narrow molecular weight distribution (polydispersity index <= 1.27). They self-assemble into stable micelles at relatively low critical micelle concentrations (0.007-0.019 mg mL(-1)) in aqueous solution. These micelles are capable of dissociating to release the encapsulated anticancer drug doxorubicin upon cathepsin B treatment. The doxorubicin release rates from PNVCLn-b-d(Phe-Lys)(1-3) micelles decreased with increasing generation of Phe-Lys dipeptide dendrons and decreasing molecular weight of PNVCL. In addition, the lower critical solution temperatures of the copolymers increased with an extension of the enzyme incubation time. The results of in vitro cytotoxicity and cell uptake experiments showed that LDBCs show no cytotoxicity even at a high LDBC concentration of 0.4 mg mL(-1) and the drug-loaded micelles can be enriched in tumor cells. Such smart copolymers could be efficiently used in targeted therapy systems. (c) 2021 Society of Industrial Chemistry.