Fabrication of Thermosensitive Cyclic Brush Copolymer with Enhanced Therapeutic Efficacy for Anticancer Drug Delivery

Abstract

Adaptation of cyclic brush polymer for drug delivery applications remains largely unexplored. Herein, cyclic brush copolymer of poly(2-hydroxyethyl methacrylate-g-poly(N-isopropylacrylamide-st-N-hydroxyethylacrylamide)) (cb-P(HEMA-g-P(NIPAAm-st-HEAAm))), comprising a cyclic core of PHEMA and thermosensitive brushes of statistical copolymer of P(NIPAAm-st-HEAAm), is designed and synthesized successfully via a graft-from approach using atom transfer free radical polymerization from a cyclic multimacroinitiator. The composition of the brush is optimized to endow the resulting cyclic brush copolymer with a lower critical solution temperature (LCST) slightly above the physiological temperature, but lower than the localized temperature of tumor tissue, which is suitable for the hyperthermia-triggered anticancer drug delivery. Critical aggregation concentration determination reveals better stability for the unimolecular nanoparticle formed by the cyclic brush copolymer than that formed by the bottlebrush analogue. The dramatically increased size with elevated temperatures from below to above the LCST confirms hyperthermia-induced aggregation for both formulations. Such structural destabilization promotes significantly the drug release at 40 °C. Most importantly, the drug-loaded cyclic brush copolymer shows enhanced in vitro cytotoxicity against HeLa cells than the bottlebrush counterpart. The better stability and higher therapeutic efficacy demonstrates that the thermosensitive cyclic brush copolymer is a better formulation than bottle brush copolymer for controlled drug release applications.

Hyperthermia and Temperature-Sensitive Nanomaterials for Spatiotemporal Drug Delivery to Solid Tumors

“…Followed by pioneering works of Heskins and Guillet [ 119 ] on poly- N -isopropylacrylamide (PNIPAAm), which shed light on the mechanisms underlying thermal behavior of PNIPAAm in aqueous solution or in general other LSCT polymers, this polymer became a backbone in designing thermoresponsive polymers for biomedical applications because it exhibits an LCST around 32 °C, close to physiological temperature [ 120 ].…”

Thermosensitive Nanosystems Associated with Hyperthermia for Cancer Treatment

“…These thermosensitive polymers are characterized by a reversible phase transition. At low temperatures, they are water-soluble, while above a critical transition temperature, they change their conformation and the hydrophilic/hydrophobic balance, which provokes phase separation and presence of aggregates [62,63]. Temperature-responsive amphiphilic polymers often have thermosensitive hydrophilic segments and a suitable hydrophobic segment in their structure.…”

“…Temperature-responsive amphiphilic polymers often have thermosensitive hydrophilic segments and a suitable hydrophobic segment in their structure. An example of this type of polymer is the family of poly-polymers (N-substituted acrylamide), as the poly(N-isopoprylacrylamide) (pNIPAAm) [63,64]. Hruby and collaborators described systems based on pNIPAAms with isotopically labeled end groups (L-tyrosinamide or diethyltriaminepentaacetic acid) designed for local radiotherapy [65].…”

Fabrication of Reduction‐Sensitive Amphiphilic Cyclic Brush Copolymer for Controlled Drug Release

“…Polymers with branched topological structures, including dendrimers, star‐shaped polymers, segmented hyperbranched polymers, and cyclic brush polymers, are a promising class of nanocarriers for controlled delivery applications due to the ability to form unimolecular nanoparticles with enhanced stability and structural integrity, which can minimize the off‐target‐associated side effect and promote the long circulation required in vivo. Among these architectures, cyclic brush polymer with uniformly radiating polymer brushes grafting from a cyclic core template is probably considered as the most unique topology, which has attracted increasing attention in recent years due to the simultaneous functionalities of the cyclic core and the polymer brushes.…”

“…Meanwhile, the preparation of stimuli‐responsive polymers that are sensitive to various biological triggers, such as temperature, pH, redox, and reactive oxygen species (ROS) has been a hot subject of research for several decades. A further integration of stimuli‐responsive polymers with the cyclic brush architectures can create novel materials with virtues from both moieties.…”