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

Abstract

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) PNVCL n -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 1 H 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 PNVCL n -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.

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

“…Although many single stimulus responsive LDBCs have been obtained, dual responsive LDBCs have been relatively underexplored, especially systems that exhibit enzyme responsive behavior. 24,28,29 There are large variations in physiological conditions between normal microenvironments and diseased sites, thus single responsive polymer materials could not achieve the desired goals in a complex physiological microenvironment. The integration of several responsive moieties within one polymer is highly desired for biomedical applications.…”

Bioresponsive Polymers for Nanomedicine—Expectations and Reality!

“…Various approaches have been adopted to accomplish this fine-tuning, such as using polymers with inherent responsive characters, installing responsive segments or linkers, and associated dynamic covalent chemistry, inducing secondary structures and related aggregation or self-assembly behavior, adopting supramolecular assembly, or a combination of these strategies. Additionally, a combination of responsive stimuli [11], such as pH-redox-sensitive [12], pH-thermosensitive [13,14], enzyme-thermoresponsive [15], and ATP-redox [16] dual-sensitive polymeric materials, have been developed to realize NMs that respond to subtle microenvironmental change in pathologic conditions. This review article summarizes several standard stimuli with biological relevance that are commonly considered in the design of bioresponsive polymers, which serves as a platform for critical discussion and highlights the gap between expectation and current reality.…”