Miktoarm Star Polymers with Environment‐Selective ROS/GSH Responsive Locations: From Modular Synthesis to Tuned Drug Release through Micellar Partial Corona Shedding and/or Core Disassembly

Abstract

Branched architectures with asymmetric polymeric arms provide an advantageous platform for the construction of tailored nanocarriers for therapeutic interventions. Simple and adaptable synthetic methodologies to amphiphilic miktoarm star polymers have been developed in which spatial location of reactive oxygen species (ROS) and glutathione (GSH) responsive entities is articulated to be on the corona shell surface or inside the core. The design of such architectures is facilitated through versatile building blocks and selected combinations of ring‐opening polymerization, Steglich esterification, and alkyne‐azide click reactions. Soft nanoparticles from aqueous self‐assembly of these stimuli responsive miktoarm stars have low critical micelle concentrations and high drug loading efficiencies. Partial corona shedding upon response to ROS is accompanied by an increase in drug release, without significant changes to overall micelle morphology. The location of the GSH responsive unit at the core leads to micelle disassembly and complete drug release. Curcumin loaded soft nanoparticles show higher efficiencies in preventing ROS generation in extracellular and cellular environments, and in ROS scavenging in human glioblastoma cells. The ease in synthetic elaboration and an understanding of structure‐property relationships in stimuli responsive nanoparticles offer a facile venue for well‐controlled drug delivery, based on the extra‐ and intracellular concentrations of ROS and GSH.

Polymersomes: Soft Nanoparticles from Miktoarm Stars for Applications in Drug Delivery

“…119−121 Such polymers find applications in a wide variety of fields such as biosensors, 122 artificial muscles, actuators, 123,124 and drug delivery. 97,125 The stimuli-responsivity has been incorporated into various copolymer architectures including miktoarm star polymers, 126,127 which can form micellar 46,128,129 or vesicular morphologies (Table 1). 34,35,37,67,72,73,79,83,86 For example, a pH-responsive PEG−PHIS 2 miktoarm star polymer was prepared using poly(L-histidine) as a biocompatible amphoteric polymer.…”

“…Incorporation of functional groups such as hydrazone (pH), − thioketal (reactive oxygen species (ROS)), , and disulfide (glutathione (GSH)) − linkers in the copolymer structure is a commonly used approach for the preparation of stimuli-responsive polymers . These chemical entities have also been combined in a single copolymer to prepare multistimuli-responsive systems. − Such polymers find applications in a wide variety of fields such as biosensors, artificial muscles, actuators, , and drug delivery. , The stimuli-responsivity has been incorporated into various copolymer architectures including miktoarm star polymers, , which can form micellar ,, or vesicular morphologies (Table ). ,,,,,,,, For example, a pH-responsive PEG–PHIS 2 miktoarm star polymer was prepared using poly­( l -histidine) as a biocompatible amphoteric polymer .…”

“…1,45 Polymeric micelles from amphiphilic copolymers with hydrophilic fractions of ∼0.5 or higher have been widely studied for the delivery of hydrophobic drugs. 28,33,46 Due to lower hydrophobic fractions compared to polymersomes (hydrophilic mass fraction between 0.25 and 0.45), the critical aggregation concentrations (CACs) in micelles are higher, which can generally lead to lower stability in the biological environment upon dilution. 32 Because of their low CACs and chain exchange dynamics, polymersomes have slower separation and decomposition rates and long cargo retention.…”

2D and 3D Covalent Organic Frameworks: Cutting-Edge Applications in Biomedical Sciences

“…Currently, stimuli-responsive systems and materials are extensively explored for drug delivery. − Stimuli-responsiveness can be classified into two groups of internal (temperature, pH, enzyme, glucose, reactive oxygen species (ROS), glutathione (GSH)) and external (light, ultrasound, mechanical, electrical field, and magnetic field) . GSH-responsive nanocarriers based on materials have been evaluated to improve the accumulation and retention of drugs in tumors and other injured cells, which display overexpression of GSH.…”

Synthesis of multiple stimuli-responsive degradable block copolymers via facile carbonyl imidazole-induced postpolymerization modification

“…5–7 Acid-labile and disulfide linkages are the most studied cleavable linkages in the construction of SRD-exhibiting nanoassemblies. 8–16 High redox potentials caused by the higher concentration of glutathione (GSH) in cancer cells, 17–19 as well as acidic pH of tumor tissue and endosomes/lysosomes, 20,21 have been exploited as endogenous triggers to destabilize ABP-based nanoassemblies and thus enhance the release of therapeutic agents. In addition, light-cleavable linkages such as o -nitrobenzyl and coumarin groups allow for the spatial and temporal control of release kinetics.…”