Synthesis of Y-shaped poly(solketal acrylate)-containing block copolymers and study on the thermoresponsive behavior for micellar aggregates

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Abstract

One novel type of Y-shaped amphiphilic copolymers with two hydrophobic poly(solketal acrylate) (PSA) branches and one hydrophilic monomethoxy poly(ethylene glycol) (MPEG) block was synthesized by atom transfer radical polymerization (ATRP). These Y-shaped polymers can disperse in aqueous media to self-assemble into micellar aggregates with a spherical core–shell structure. The aqueous copolymer solutions exhibited transmittancy transition in the temperature range of 30–60 °C via optical transmittance measurements. An interesting thermo-dependent size of the micellar aggregates was observed by dynamic light scattering techniques and transmission electron microscopy, which showed that the micelle diameters were decreased with temperature increasing. The nile red release from the micelles at 25 °C and 37 °C under various pHs showed that temperature has great influence on release behavior. With good biocompatibility, the micellar aggregates formed from MPEG-block-(PSA)2 may serve as one promising thermosensitive nanovehicle for targeted drug delivery.

Graphical abstract

MPEG-block-(PSA)2 copolymer micelles represent an attractive temperature responsive olume transition property.

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Research highlights

► The thermoresponsive polymeric micelles from Y-shaped polymers MPEG-block-(PSA)2. ► The micelle sizes were decreased with temperature increasing. ► Nile red release from the micelles occurred at 37 °C rather than 25 °C.

Introduction

Stimuli-responsive polymers, especially amphiphilic stimuli-responsive block copolymers are currently receiving much attention, because besides their unique properties of self-assembling into nanoscaled aggregates or micelles with a hydrophilic outer corona and a closely packed hydrophobic core in selective environment to serve as excellent nanocarriers, more importantly, they can take on an active role to release the loaded molecules at the target site under appropriate stimuli such as temperature, pH, ionic strength, magnetic field, and ultraviolet light [1], [2], [3], [4]. In recent years, a variety of “intelligent” or “smart” amphiphilic polymers responding to stimuli have been successfully explored to better meet the requirement of the applied biological science [5], [6], [7], [8]. Among these internal or external stimuli, temperature is one of the best stimuli in terms of easy and safe medical applications. Therefore, developments of novel thermoresponsive polymers are an extremely important subject in the field of drug delivery, immobilized enzyme reactor and attachment/detachment of cells [9], [10], [11].

Poly(N-isopropyl acrylamide) (PNIPAM) and its copolymers are well-known and intensively investigated thermoresponsive polymers because their low critical solution temperature (LCST) in water is close to body temperature and their robust transition ensures relatively insensitive to the changes in concentration or pH [12], [13], [14], [15]. Very recently, Lutz and his coworkers described the oligo(ethylene glycol) methacrylate (OEGMA) copolymers and their analogues as one type of noteworthy thermoresponsive alternatives [16], [17], [18], due to their nanoparticle aggregates readily redissolving in aqueous solution upon cooling without any noticeable hysteresis [19]. These thermosensitive polymers are able to undergo phase transition in water from a soluble to an insoluble state when the temperature is above their LCST, thus generating driving force for the self-assembly of polymers [20], [21] or inducing further aggregation on the basis of the strengthened hydrophobic interaction [22], [23]. Although great progress has been achieved in this field, exploring novel thermoresponsive polymers still remains as a challenge.

Poly(solketal acrylate) (PSA) as hydrophobic polymer can be hydrolyzed under acidic conditions to remove ketal groups and converted to water-soluble poly(2,3-dihydroxypropyl acrylate) (PHPA) bearing double hydroxyl groups in each repeating unit [24], [25], [26]. Compared to the intensive studies on PHPA in the field of magnetic nanocomposites and functional modification [27], [28], [29], PSA itself did not attract much attention but as PHPA polymer precursor. In fact, PSA polymer has some noticeable advantages in the aspect of chemical synthesis. For instance, the starting materials, such as glycerol and acetone, are low-price and biocompatible, the synthesis procedure of the monomer SA is well-operation with high yield and the polymerization reaction is ease to occur. Due to PSA polymer bearing ketal groups, in the previous work, our group reported their pH-responsive behavior of the polymeric micelles formed from the amphiphilic block polymers with PSA as hydrophobic block and monomethoxy poly(ethylene glycol) (MPEG) as hydrophilic block [30]. During further study, we unexpectedly observed the thermo-induced release behavior of the encapsulated molecule from these polymeric micelles. To the best of our knowledge, few studies have been reported for the block copolymers composed of MPEG and PSA exhibiting thermoresponsive behavior in aqueous solution. Therefore, this promising result promotes us to investigate the thermoresponsive property of PSA-containing polymers in order to develop novel thermosensitive materials.

Recent research has revealed that the precise nature of the block copolymer architectures played an important role in determining their aqueous solution properties. Nonlinear asymmetric (AB2 or AB3 type) block copolymers exhibited fundamentally different micellization behavior compared to the corresponding linear AB diblocks [31], [32], [33], [34]. This provoked considerable interest in the preparation of a variety of miktoarm copolymers with varying arm numbers, chemical composition, and chain topology. In this report, we designed and synthesized new Y-shaped amphiphilic copolymers MPEG-block-(PSA)2 via atom transfer radical polymerization (ATRP) using MPEG-Br2 as macroinitiators. As compared to the traditional linear copolymer MPEG-block-PSA, the different thermoresponsive behavior of the micellar aggregates from these Y-shaped polymers was investigated. The release of nile red as probe molecule from the resulting Y-shaped copolymer micelles was detected under different temperature and pHs. A cytotoxicity study of these copolymers was examined to reveal its biocompatibility. These amphiphilic Y-shaped PSA-containing copolymers with promising thermosensitivity discovered for the first time would expand their potential applications in the field of biomedical materials.

Section snippets

Materials

Monomethoxy poly(ethylene glycol) MPEG2000 purchased from Fluka, was dried by azeotropic distillation with toluene, and residual toluene was removed under high vacuum prior to use. CuBr purchased from Aldrich, was purified by stirring in acetic acid overnight, followed by washing with ethanol and diethyl ether, and dried in vacuum. Triethylamine (TEA) and methylene dichloride (CH2Cl2) were dehydrated with KOH and CaCl2 overnight and distilled, respectively. Toluene was dried using sodium with

Preparation of macroinitiator MPEG-Br2 containing double initiation points

The macroinitiator MPEG-Br2 was synthesized in four steps as shown in Scheme 1. In the presence of catalytic amount of p-toluene sulfonic acid, MPEG 2000 reacted with excess IPL-bis-MPA which was the product of the first step by the reaction of 2,2-bis(methoxy)propionic acid with 2,2-dimethoxypropane, to afford IPL-MPEG with good yield. Each 13C NMR signal of IPL-MPEG in Fig. S1 was reasonably attributed, and the absence of the signal for the carbon atom linking with the end hydroxyl group of

Conclusions

We found one promising thermosensitivity of the polymeric micelles from the readily available amphiphilic Y-shaped polymers comprising of MPEG as hydrophilic block and PSA as hydrophobic block at the Y-shaped branches. These amphiphilic polymers self-assembled to form core-corona type spherical micellar aggregates with mean diameter range of 100–200 nm in aqueous solution. As temperature increased, the transmittancy of the micellar solution was changed with the particle sizes decreasing.

Acknowledgments

This work was supported by National Natural Science Foundation of China (NSFC, Grant No. 20804003), Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry and Chinese Universities Scientific Fund. We also thank Professor Shu Wang and Dr. Libing Liu (Institute of Chemistry, Chinese Academy of Sciences) for their generous help.

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