pH-Responsive Amphiphilic Polyether Micelles with Superior Stability for Smart Drug Delivery

Abstract

Despite widespread interest in the amphiphilic polymeric micelles for drug delivery systems, it is highly desirable to achieve high loading capacity and high efficiency to reduce the side effects of therapeutic agents while maximizing their efficacy. Here, we present a novel hydrophobic epoxide monomer, cyclohexyloxy ethyl glycidyl ether (CHGE), containing an acetal group as a pH-responsive cleavable linkage. A series of its homopolymers, poly(cyclohexyloxy ethyl glycidyl ether)s (PCHGEs), and block copolymers, poly(ethylene glycol)-blockpoly(cyclohexyloxy ethyl glycidyl ether)s (mPEG-b-PCHGE), were synthesized via anionic ring-opening polymerization in a controlled manner. Subsequently, the self-assembled polymeric micelles of mPEG-b-PCHGE demonstrated high loading capacity, excellent stability in biological media, tunable release efficiency, and high cell viability. Importantly, quantum mechanical calculations performed by considering prolonged hydrolysis of the acetal group in CHGE indicated that the CHGE monomer had higher hydrophobicity than three other functional epoxide monomer analogues developed. Furthermore, the preferential cellular uptake and in vivo therapeutic efficacy confirmed the enhanced stability and the pH-responsive degradation of the amphiphilic block copolymer micelles. This study provides a new platform for the development of versatile smart polymeric drug delivery systems with high loading efficiency and tailorable release profiles.

pH-Responsive Nanocarriers in Cancer Therapy

“…Of these, hydrophobic interactions were found to strongly influence the stability and loading efficiency of micelles. Accordingly, Son et al [ 61 ] synthesized PMs using block copolymers, poly(ethylene glycol)-blockpoly(cyclohexyloxy ethyl glycidyl ether)s (mPEG-b-PCHGE) with an acetal group as the pH-cleavable linkage. In vitro release results showed higher stability and better pH responsiveness due to the addition of the hydrophobic CHGE block.…”

Dynamics in Controllable Stimuli-Responsive Self-Assembly of Polymer Vesicles with Stable Radical Functionality

“…Over the past decade, research interest in cancer treatment is growing to overcome conventional treatment defects and side effects . In many strategies, environmentally sustainable and responsive polymeric nanocarriers are promising for better cancer treatment due to target-specific delivery of therapeutic agents and reduced side effects. , Hence, the functionalization capabilities of polymers make them more interesting and attractive as responsive materials in cancer therapy. − Stimuli-responsive supramolecular nanomaterials that respond to chemical and/or physical stimuli are called “smart” biomaterials and are versatile in their applications . Especially, self-assembled polymer nanomaterials are of great interest and offer specific applications in biomedical fields such as high loading, prolonged circulation, transportation, and stimuli-triggered controlled release of drugs. ,− For this purpose, various polymer nanomaterials with morphologies of spheres, micelles, vesicles, worm-like nanostructures, tubes, etc.…”

“…4−6 Stimuliresponsive supramolecular nanomaterials that respond to chemical and/or physical stimuli are called "smart" biomaterials and are versatile in their applications. 7 Especially, selfassembled polymer nanomaterials are of great interest and offer specific applications in biomedical fields such as high loading, prolonged circulation, transportation, and stimuli-triggered controlled release of drugs. 2,8−11 For this purpose, various polymer nanomaterials with morphologies of spheres, micelles, vesicles, worm-like nanostructures, tubes, etc.…”

Hydrolysis-Driven Viscoelastic Transition in Triblock Copolyether Hydrogels with Acetal Pendants

“…Herein, we present polyether-based ABA triblock copolymer hydrogels containing a poly(ethylene oxide) (PEO) midblock and a hydrophobic end-block with acetal pendant groups, which provides an ideal platform to evaluate and tailor the viscoelastic transition resulting from the hydrolytic degradation of acetal pendant groups. Endocyclic acetal-based tetrahydropyranyl glycidyl ether (TPGE) 29 and exocyclic acetal-based 1-(cyclohexyloxy)ethyl glycidyl ether (CHGE) 30 were employed as two types of representative acetal pendant groups for the ABA triblock copolymers. Here, the endocyclic acetal refers to the acetal linkages that are a part of the ring structure as in TPGE.…”

“…Hydrophobic epoxide monomers containing acetal linkages, TPGE and CHGE, were prepared by reacting glycidol with 2,3-dihydropyran and cyclohexyl vinyl ether, respectively, as previously reported by our group (Scheme ). , Anionic ring-opening polymerization of TPGE and CHGE were performed using α,ω-hydroxy-terminated PEO ( M n = 20 kDa), resulting in a series of symmetric ABA-type triblock copolymers, as summarized in Table . The chemical structures of the acetal glycidyl ether monomers and the resulting triblock copolyethers were successfully resolved by 1 H NMR spectroscopy (Figure ).…”