Redox-Responsive Core-Cross-Linked Micelles of Miktoarm Poly(ethylene oxide)-b-poly(furfuryl methacrylate) for Anticancer Drug Delivery

Abstract

The physiological instability of nanocarriers, premature drug leakage during blood circulation, and associated severe side effects cause compromised therapeutic efficacy, which have significantly hampered the progress of nanomedicines. The cross-linking of nanocarriers while keeping the effectiveness of their degradation at the targeted site to release the drug has emerged as a potent strategy to overcome these flaws. Herein, we have designed novel (poly(ethylene oxide)) 2 -b-poly(furfuryl methacrylate) ((PEO 2K ) 2 -b-PFMA nk ) miktoarm amphiphilic block copolymers by coupling alkynefunctionalized PEO (PEO 2K -C�H) and diazide-functionalized poly(furfuryl methacrylate) ((N 3 ) 2 -PFMA nk ) via click chemistry. (PEO 2K ) 2 -b-PFMA nk selfassembled to form nanosized micelles (mikUCL) with hydrodynamic radii in the range of 25∼33 nm. The hydrophobic core of mikUCL was cross-linked by a disulfide-containing cross-linker using the Diels−Alder reaction to avoid unwanted leakage and burst release of a payload. As expected, the resulting core-cross-linked (PEO 2K ) 2 -b-PFMA nk micelles (mikCCL) exhibited superior stability under a normal physiological environment and were de-cross-linked to rapidly release doxorubicin (DOX) upon exposure to a reduction environment. The micelles were compatible with HEK-293 normal cells, while DOX-loaded micelles (mikUCL/DOX and mikCCL/DOX) induced high antitumor activity in HeLa and HT-29 cells. mikCCL/ DOX preferentially accumulated at the tumor site and was more efficacious than free DOX and mikUCL/DOX for tumor inhibition in HT-29 tumor-bearing nude mice.

Single Functional Group Platform for Multistimuli Responsivities: Tertiary Amine for CO2/pH/ROS-Triggered Cargo Release in Nanocarriers

“…For example, keeping a composition similar to that of a linear AB copolymer, the molecular weights of the individual B arms are lowered in AB n -type arrangements, leading to reduced chain entanglement. Therefore, core–shell formulations from the aqueous self-assemblies of miktoarm stars possess highly beneficial traits, including small dimensions, low critical micelle concentrations (CMC), denser corona, enhanced stability, high encapsulation efficiencies, and so forth. − In addition, due to the ease of introducing different polymeric arms, many studies have focused on personalizing miktoarm copolymers with desired functions for better outcomes in intended applications. − In the current study, we utilized the branched architecture to design a stimuli-responsive miktoarm polymer with a tertiary amine group that became an intricate part of the micelle hydrophobic core, offering tuned responsiveness to various stimuli (CO 2 , pH, ROS, and ROS + CO 2 ) and resulting in controlled release of Cur.…”

UV Irradiation-Induced Cyclic-to-Linear Topological Changes of a Light/pH Dual-Sensitive Cyclic Copolymer for Enhanced Drug Delivery

“…Polymeric micelles represent probably one of the most studied nanocarriers for anticancer drug delivery owing to their notable advantages. − However, compromised micelle stability in the blood circulation upon intravenous injection due to massive dilution by body fluids and blood and interactions with a variety of biomolecules and extraneous factors leads to leakage and premature diffusion of encapsulated therapeutics resulting in toxicity to normal tissues and significantly compromised therapeutic efficiency at the focal site. , Polymers with advanced topologies, including star-shaped, , (hyper)­branched, dendritic, bottlebrush, and cyclic structures, , have been reported to endow the resulting polymeric self-assemblies with enhanced colloidal stability for long blood circulation in vivo. Among these reported advanced topological architectures, cyclic and its derived topologies have attracted considerable interest in the past decade because of the endless chain structure-associated unique properties that are quite different from those of linear counterparts .…”