The effect of photoisomerization on the enzymatic hydrolysis of polymeric micelles bearing photo-responsive azobenzene groups at their cores

Abstract

The design of stable polymeric micelles that can respond to specific stimuli is crucial for the development of smart micellar nanocarriers that can release their active cargo selectively at the target site, thus diminishing the therapeutic limitations due to non-selective damage to healthy tissues. Here we report the design and synthesis of photo- and enzyme-responsive amphiphilic PEG-dendron hybrids bearing one, two or four enzymatically cleavable azobenzene end-groups. These dual-responsive hybrids can respond to light through the reversible isomerization of the azobenzene end-groups from the non-polar trans isomer to the highly polar cis isomer and vice versa, upon UV and visible irradiation, respectively. The high structural precision of these hybrids, which emerges from the dendritic architecture, enabled a detailed study of the photoisomerization of the azobenzene end-groups with high molecular resolution. Remarkably, although the transition from trans-to-cis led to a significant increase in the polarity of the micellar cores, the micelles remained stable. Our kinetic studies show that although the trans isomer is a better substrate for the activating enzyme, the UV induced formation of the cis azobenzene end-groups led to significant acceleration of the enzymatic hydrolysis of the end-groups. These results provide strong indication that the enzyme cannot reach the core of the micelles and instead the end-groups have to leave the hydrophobic core in order to be exposed on the micelle's surface or even leave the micelle in order to allow their cleavage by the activating enzymes.

Modular Synthetic Approach for Adjusting the Disassembly Rates of Enzyme-Responsive Polymeric Micelles

“…mPEG 5 kDa -allyl and mPEG 5 kDa -NH 2 were prepared as was described in a previously reported procedure …”

“…mPEG 5 kDa -allyl and mPEG 5 kDa -NH 2 were prepared as was described in a previously reported procedure. 29 mPEG 5 kDa -Propargyl. Methoxy poly(ethylene glycol) (M n = 5 kDa, 5.00 g, 1 mmol), KOH (1.68 g, 30 mmol, 30 equiv), and 80% propargyl bromide in toluene (3.25 mL, 30 mmol, 30 equiv) were reacted in toluene (50 mL) following a previously reported procedure.…”

Self-Assembly and Enzyme Responsiveness of Amphiphilic Linear-Dendritic Block Copolymers Based on Poly(N-vinylpyrrolidone) and Dendritic Phenylalanyl-lysine Dipeptides

“…Because of good antifouling property, low toxicity, and biocompatibility, poly(ethylene glycol) (PEG) is often used as a hydrophilic material, is modified to the surface of nanocarriers to increase their stability, resist protein adsorption in vivo, and prolong the circulation of nanocarriers in the body [30,31]. Consequently, most of enzyme-responsive LDBCs used PEG as a hydrophilic linear link to hydrophobic branches which can be hydrolyzed by lipase or amidase [32,33,34]. However, a large number of studies and clinical results have shown that PEG materials are slowly showing many shortcomings.…”

Triple responsive block copolymers combining pH‐responsive, thermoresponsive, and glucose‐responsive behaviors

“…[1][2][3][4][5] By selectively incorporating certain functional groups, such responsive materials can undergo a number of property changes as a result of external influences, including non-chemical stimuli such as light 6 or temperature, [7][8][9] or through chemical stimuli such as changes in pH, 6,8,10 redox reactions, [11][12][13][14] or dynamic-covalent, 15 and supramolecular interactions. 2,[16][17][18] Photoresponsive materials often demonstrate reversible isomerization upon irradiation and commonly include materials with azobenzene moieties 19,20 or spiropyrans. 21 Polymers with pH-responsive characteristics most often contain weak acid or base functional groups that lead to ionization or neutralization when exposed to a change in pH.…”