Shell Cross-linked Micelles Research Articles

Poly(norbornene) block copolymer-based shell cross-linked micelles with Co(iii)–salen cores

A series of poly(norbornene) based amphiphilic triblock copolymers containing covalently attached salen ligands in the hydrophobic block, a cinnamate group-containing middle block and a poly(ethylene glycol) methyl ether-containing repeat unit as the hydrophilic block have been synthesized using living ring-opening metathesis polymerization. Micellar assemblies constructed of these copolymers were stabilized by cross-linking of the cinnamate-containing middle block using UV irradiation. The resulting shell cross-linked micelles (SCMs) have salen ligands selectively located within the hydrophobic core that are modified further by metal complexation with cobalt ions to produce SCMs core supported Co(III)-salen catalysts. The catalytic activities of these SCM catalysts were systematically investigated by hydrolytic kinetic resolution of epichlorohydrin. It was found that the composition of the copolymers and the size of SCM have substantial influences on the catalytic activity of SCMs catalysts.

Tunable dual-emitting shell-crosslinked nano-objects as single-component ratiometric pH-sensing materials.

Dual-emitting photonic nano-objects that can sense changes in the environmental pH are designed based on shell-crosslinked micelles assembled from amphiphilic block copolymers and crosslinked with pH-insensitive chromophores. The chromophoric crosslinkers are tetra-functionalized pyrazine molecules that bear a set of terminal aliphatic amine groups and a set of anilino amine groups, which demonstrate morphology-dependent reactivities towards the poly(acrylic acid) shell domain of the nano-objects. The extent to which the anilino amine groups react with the nano-object shell is shown to affect the hypsochromic shift (blue-shift). The ratio of fluorescence intensity at 496 nm over that of 560 nm is dependent upon the solution pH. We report, herein, observations on the pH-sensitive dual-emission photophysical properties of rod-shaped or spherical nano-objects, whose shell domains offer two distinct platforms for amidation reactions to occur-through formation of activated esters upon addition of carbodiimide or pre-installation of activated ester groups. We demonstrate that physical manipulations (changes in morphology or particle dimensions) or chemical manipulations of the crosslinking reaction (the order of installation of activated esters) lead to fine tuning of dual-emission over ca. 60 nm in a physiologically relevant pH range. Rod-shaped shell-crosslinked nanostructures with poly(p-hydroxystyrene) core show blue-shift as a function of increasing pH while spherical shell-crosslinked nanostructures with polystyrene core and poly(ethylene oxide) corona exhibit blue-shift as a function of decreasing pH.

Synthesis of zwitterionic shell cross-linked micelles with pH-dependent hydrophilicity

Shell cross-linked (SCL) micelles were constructed based on the diblock copolymer poly( t-butyl acrylate)- b-poly(2-dimethylamino)ethyl methacrylate (P tBA- b-PDMAEMA) which was synthesized by sequential atom transfer radical polymerization (ATRP). Using trifluoroacetic acid (TFA) to hydrolyze the SCL micelles, zwitterionic SCL micelles were prepared. The hydrophilicity, size, and softness of the core and the shell of the micelles can be tuned independently by adjusting the pH. At low pH (3.4), the micelles turned into nanoparticles with compact cores and swollen shells; at neutral medium (6.8), the SCL micelles were entirely hydrophilic; at pH 11.6, a double-layer cage-like nanostructure was observed. Moreover, the inner and outer layers of the nanocage had opposite behaviors to the pH stimulus. The existence of tunable nanostructures of these zwitterionic SCL micelles could be proved by the ratio of gyration radius ( R g) to hydrodynamic radius ( R h) and SEM micrographs.

Fabrication of multifunctional shell cross-linked micelles for targeting drug release

Thermosensitive amphiphilic poly(N-acroyloxysuccinimide)-b-poly(N-isopropylacrylamide)-b-poly(e-caprolactone) triblock copolymer was synthesized via the combination of reversible addition fragmentation chain transfer and ring-opening polymerization techniques. Shell cross-linked micelle (SCL) was further developed by the addition of cystamine as a di-functional cross-linker into the micellar solution. The persistence of regularly spherical shape against media change demonstrated locked micellar structure resulting from sufficient shell cross-linking. The lower critical solution temperature of the resulting SCL micelles was around 38 °C. The in vitro drug release study was carried out to illustrate the temperature-responsive drug release behaviors. To enhance the internalization to tumor cells, transferring (Tf) was further conjugated to the SCL micelles, and endocytosis experiments further confirmed the efficient uptake of Tf-SCL micelles by tumor cells, indicating that the Tf-SCL micelles would be a promising candidate for tumor-targeted drug delivery.

Application of the biodegradable diblock copolymer poly(L‐lactide)‐block‐poly(L‐cysteine): Drug delivery and protein conjugation

AbstractA novel approach to self‐assembled and shell‐crosslinked (SCL) micelles from the diblock copolymer poly(L‐lactide)‐block‐poly(L‐cysteine) to be used as drug and protein delivery carriers is described. Rifampicin was used as a model drug. The drug‐loaded SCL micelles were obtained by self‐assembly of the copolymer in the presence of the drug in aqueous media. Their morphology and size were studied with dynamic light scattering and field emission scanning electron microscopy. The rifampicin loading capacity and encapsulation efficiency were studied with ultraviolet–visible spectrophotometry. The drug‐release rate in vitro depended on the oxidizing and reducing environment. Moreover, a straightforward approach to the conjugation of the copolymer with bovine serum albumin (BSA) was developed, and a gel electrophoresis test demonstrated that this conjugated BSA could be reversibly released from the copolymer substrate under reducing conditions. In conclusion, this L‐cysteine copolymer can be used in drug delivery and in protein fixation and recovery. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010

Reversible Interpolyelectrolyte Shell Cross-Linked Micelles from pH/Salt-Responsive Diblock Copolymers Synthesized via RAFT in Aqueous Solution

Herein we report the synthesis and characterization of a series of pH reversible shell cross-linked micelles. A series of novel pH/salt-responsive block copolymers of poly(sodium 2-acrylamido-2-methyl-1-propanesulfonate-block-N-acryloyl-l-alanine) (P(AMPS-b-AAL)) were synthesized utilizing aqueous reversible addition−fragmentation chain transfer (RAFT) polymerization. Micellization of P(AMPS-b-AAL) is induced by rendering the PAAL block hydrophobic through protonation of the carboxylic acid (pH 1−3). The pH at which micelle formation occurs and the hydrodynamic diameters of the resultant micelles are dictated by block copolymer composition and electrolyte concentration. The anionic PAMPS micelle shells were subsequently cross-linked with a RAFT synthesized cationic homopolymer of either poly(N-[3-(dimethylamino)propyl]acrylamide) (PDMAPA, pKa = 8.5) or poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA, pKa = 7.3). Upon deprotonation of the PAAL block, these cross-linked micelles swell but remain stable and intact. Significantly, the reversibility of the cross-linking was determined to be tunable by utilizing the different cationic homopolymers for cross-linking. This was demonstrated by increasing the pH above the pKa of the cationic homopolymer cross-linker, resulting in deprotonation of the cationic cross-linker and dissociation of the cross-linked micelles.

Synthesis of Thermoresponsive Shell Cross-Linked Micelles via Living Cationic Polymerization and UV Irradiation

A series of well-defined thermoresponsive poly(2-ethoxyethyl vinyl ether)-block-poly(2-hydroxyethyl vinyl ether) (PEOVE-b-PHOVE) block copolymers have been synthesized via sequential living cationi...

Fabrication of core or shell reversibly photo cross-linked micelles and nanogels from double responsive water-soluble block copolymers

Poly(butanedioic acid, 1-[3-[(2-methyl-1-oxo-2-propen-1-yl)oxy]propyl] ester)-b-poly(methoxydi(ethylene glycol) methacrylate- co-4-methyl-[7-(methacryloyl)oxyethyloxy] coumarin) (PSPMA-b-P(DEGMMA- co-CMA)) block copolymer was synthesized via atom transfer radical polymerization (ATRP). The temperature and pH responsive micellization behaviors of PSPMA-b-P(DEGMMA- co-CMA) were investigated to obtain P(DEGMMA- co-CMA)-core and PSPMA-core micelles. After the two types of micelles were exposed to 365 nm UV light, core cross-linked (CCL) micelles and shell cross-linked (SCL) micelles were facilely prepared. The photo cross-linking was proved to be reversibly controlled under alternative irradiation of 365 nm and 254 nm UV light. More interestingly, block copolymer nanogels were fabricated by translating the hydrophobic core of the CCL and SCL micelles into hydrophilic via adjusting the temperature and pH. The sizes of the block copolymer nanogels can be facilely controlled by UV light irradiation. The introduction of reversibly photo cross-linkable groups into the double responsive block copolymers provides a novel approach to develop more sophisticated, controllable, and smarter nanocarriers that might have great potentials in biomedical applications.

Synthesis and application of pH-responsive branched copolymer nanoparticles (PRBNs): a comparison with pH-responsive shell cross-linked micelles

pH-responsive polymers are both a fascinating and fundamentally important class of polymer. The ability to change their aqueous solution properties and behavior in response to simple external stimuli—that is, the addition of acid or base—places them uniquely as: (i) ‘building blocks’ for the fabrication of higher-order materials via self-assembly, (ii) controllable encapsulation and release devices and, (iii) useful synthetic mimics of highly complex natural biological systems. The fabrication of pH-responsive branched copolymer nanoparticles (PRBNs) which are capable of reversibly forming distinct ‘core–shell’ morphologies is an emerging class of material. In this highlight, we discuss key advances in the synthesis, characterization and application of branched pH-responsive copolymer nanoparticles and place these developments in the context of seemingly similar structures—most notably shell cross-linked micelles. We also speculate as to the scope, and limitations, of these branched materials in various commercial and fundamental applications.

Marrying click chemistry with polymerization: expanding the scope of polymeric materials

Click chemistry constitutes a class of reactions broadly characterized by efficiency, selectivity, and tolerance to a variety of solvents and functional groups. By far the most widely utilized of these efficient transformation reactions is the Cu(I)-catalyzed azide-alkyne cycloaddition. This reaction has been creatively employed to facilitate the preparation of complex macromolecules, such as multiblock copolymers, shell or core cross-linked micelles, and dendrimers. This critical review highlights the application of click chemistry, in particular the Cu(I)-catalyzed azide-alkyne cycloaddition, to the synthesis of a wide variety of new materials with possible uses as drug delivery agents, tissue engineering scaffolds, and dispersible nanomaterials (83 references).

Temperature and pH Double Responsive Hybrid Cross-Linked Micelles Based on P(NIPAAm-co-MPMA)-b-P(DEA): RAFT Synthesis and “Schizophrenic” Micellization

Poly(N-isopropylacrylamide-co-3-(trimethoxysilyl)propyl methacrylate)-b-poly(2-(diethylamino)ethyl methacrylate) (P(NIPAAm-co-MPMA)-b-P(DEA)) copolymer was synthesized by reversible addition−fragmentation chain transfer (RAFT) polymerization. The temperature and pH responsive schizophrenic micellization behaviors of P(NIPAAm-co-MPMA)-b-P(DEA) and the cross-linking of P(NIPAAm-co-MPMA) blocks using inorganic silica-based cross-linking strategy were investigated in detail. Transmission electron microscopy (TEM) showed that the resultant core cross-linked (CCL) and shell cross-linked (SCL) micelles displayed regular spherical shapes with different sizes in N,N′-dimethylformamide (DMF) and aqueous media. The structure changes of CCL and SCL micelles at different pHs and temperatures were characterized by 1H NMR. Optical absorption measurements showed that the lower critical solution temperatures (LCSTs) of the CCL and SCL micelles were 37.5 and 40.5 °C, respectively. In vitro drug release study showed that th...

Fabrication of Two Types of Shell-Cross-Linked Micelles with “Inverted” Structures in Aqueous Solution from Schizophrenic Water-Soluble ABC Triblock Copolymer via Click Chemistry

A well-defined ABC triblock copolymer, poly(2-(2-methoxyethoxy)ethyl methacrylate)-b-poly(2-(dimethylamino)ethyl methacrylate)-b-poly(2-(diethylamino)ethyl methacrylate) (PMEO2MA-b-PDMA-b-PDEA), was synthesized via sequential atom transfer radical polymerization using ethyl 2-bromoisobutyrate as the initiator. Reacting the triblock precursor with propargyl bromide in anhydrous tetrahydrofuran yielded PMEO2MA-b-P(DMA-co-QDMA)-b-PDEA triblock copolymer with "clickable" moieties, where QDMA was quaternized DMA residues. PMEO2MA-b-P(DMA-co-QDMA)-b-PDEA triblock copolymer exhibited "schizophrenic" micellization behavior in aqueous solution, forming three-layer onion-like PMEO2MA-core and PDEA-core micelles upon proper adjustment of the solution pH and temperature. For temperature-induced formation of PMEO2MA-core micelles at acidic pH, the critical micellization temperature can be tuned by incorporating oligo(ethylene glycol) methyl ether methacrylate (OEGMA; the mean degree of polymerization was 8-9) residues into the PMEO2MA block, shifting from 38 to 43 degrees C as the OEGMA contents varied in the range of 0-10 mol %. In both types of micelles, the inner shell layer consisted of the middle P(DMA-co-QDMA) segment. Subsequently, cross-linking with tetra(ethylene glycol) diazide via click chemistry in the presence of copper catalysts led to the facile preparation of two types of shell-cross-linked (SCL) micelles with "inverted" structures in purely aqueous solution. The cores and coronas of SCL micelles exhibited multiresponsive swelling/shrinking and collapse/aggregation behavior, respectively. To the best of our knowledge, this represents the first report of the fabrication of two types of SCL micelles with inverted structures from a single schizophrenic water-soluble triblock copolymer in purely aqueous solution.

Covalently stabilized temperature and pH responsive four-layer nanoparticles fabricated from surface ‘clickable’ shell cross-linked micelles

Alkynyl-terminated double hydrophilic ABC triblock copolymer, poly(oligo(ethylene glycol) monomethyl ether methacrylate)-b-poly(2-(dimethylamino) ethyl methacrylate)-b-poly(2-(diethylamino) ethyl methacrylate) (alkynyl-POEGMA-b-PDMA-b-PDEA), was synthesized via atom transfer radical polymerization (ATRP) by sequential monomer addition using propargyl 2-bromoisobutyrate (PgBiB) as the initiator. The obtained triblock copolymer dissolves molecularly in acidic media and self-assembles into alkynyl surface-functionalized three-layer “onion-like” micelles consisting of a PDEA core, a PDMA inner shell, and a POEGMA corona at alkaline pH. Selective cross-linking of the PDMA inner shell with 2-bis(2-iodoethoxy)ethane (BIEE) results in structurally stable and surface ‘clickable’ shell cross-linked (SCL) micelles with pH-responsive PDEA cores. This new kind of SCL micelles could be further surface functionalized or conjugated with other azido- terminated polymer chains, functional groups, or biomolecules via Click chemistry. Four layer nanoparticles (SCL-PNIPAM) which have pH-responsive PDEA cores and temperature responsive PNIPAM outer coronas were fabricated from surface ‘clickable’ shell cross-linked (SCL) micelles and azide-terminated poly(N-isopropylacrylamide) (PNIPAM-N3) using Click chemistry. These novel four layer nanoparticles might act as suitable nano-sized drug delivery vehicles for the encapsulation and release of hydrophobic drugs as a function of either temperature or pH of the environment

Facile 'One-Pot' Preparation of Reversible, Disulfide-Containing Shell Cross-Linked Micelles from a RAFT-Synthesized, pH-Responsive Triblock Copolymer in Water at Room Temperature

A pH-responsive triblock copolymer, α-methoxy poly(ethylene oxide)-b-poly(N-(3-aminopropyl) methacrylamide)-β-poly(2-(diisopropylamino)ethyl methacrylate) (mPEO-PAPMA-PDPAEMA), was synthesized via aqueous RAFT polymerization. This triblock copolymer dissolves in aqueous solution at low pH (<5.0) due to protonation of primary amine residues on the PAPMA block and tertiary amine residues on the PDPAEMA block. Above pH 6.0, the copolymer unimers self-assemble into micelles consisting of PDPAEMA cores, PAPMA shells, and mPEO coronas. Dynamic light scattering studies indicated a hydrodynamic diameter of 92 nm at pH 9.0. A bifunctional, reversible cross-linker, dimethyl 3,3′-dithiobispropionimidate (DTBP), was used to cross-link the micelles. The ‘one-pot’ formation of shell cross-linked (SCL) micelles was accomplished at room temperature in water by mixing the triblock copolymers and DTBP at pH 3.0, and slowly increasing the solution pH to 9.0 leading to the simultaneous formation of micelles and cross-linking. These SCL micelles are readily cleaved by the addition of the reducing agent, dithiothreitol, and can be re-cross-linked simply by exposure to air. Such SCL micelles have potential as nanocarriers for controlled release of therapeutic and diagnostic agents because the in situ cleavage of the disulfide linkages would not only allow release of bioactive agents, but also permit renal clearance of the resulting unimeric components.

Aqueous RAFT Synthesis of pH-Responsive Triblock Copolymer mPEO−PAPMA−PDPAEMA and Formation of Shell Cross-Linked Micelles

Herein we report the synthesis and characterization of polymeric cross-linking agents and novel shell cross-linked (SCL) micelles utilizing reversible addition−fragmentation chain transfer (RAFT) polymerization. A series of pH-responsive ABC triblock copolymers consisting of α-methoxypoly(ethylene oxide)-b-poly[N-(3-aminopropyl)methacrylamide]-b-poly[2-(diisopropylamino)ethyl methacrylate] (mPEO−PAPMA−PDPAEMA) have been synthesized via RAFT polymerization in aqueous media at 70 °C employing a PEO-based macro-chain transfer agent (macro-CTA). These triblock copolymers molecularly dissolve in aqueous solution at low pH (<5.0) due to protonation of primary amine residues on the PAPMA block and tertiary amine residues on the PDPAEMA block. Above pH 6.0, the polymers self-assemble into micelles consisting of PDPAEMA cores, PAPMA shells, and mPEO coronas. Hydrodynamic dimensions of the triblock copolymer micelles depend on both triblock copolymer composition and solution pH. Narrowly dispersed poly(N-isopropylacrylamide) was synthesized utilizing the difunctional CTA, 2-(1-carboxy-1-methylethylsulfanylthiocarbonylsulfanyl)-2-methylpropionic acid (CMP). The chain ends of the PNIPAM were converted from carboxylic acids to N-hydroxysuccinimidyl esters (NHS) through dicyclohexylcarbodiimide (DCC) coupling, yielding an amine-reactive polymeric cross-linking agent, NHS−PNIPAM−NHS. SCL micelles were attained via reaction of PAPMA (shell) amine functionality with NHS-functionalized PNIPAM. These SCL micelles swell when the solution pH is lowered below the pKa of the PDPAEMA block. The polymeric cross-linking agent NHS−PNIPAM−NHS synthesized in this work has inherent temperature-responsive segments and a cleavable trithiocarbonate unit which have future potential in mediating drug delivery from SCL micelles.

Preparation of Shell Cross-Linked Thermoresponsive Micelles as well as Hollow Spheres Based on P(NIPAAm-co-HMAAm-co-MPMA)-b-PCL

A novel amphiphilic block copolymer poly(N-isopropylacrylamide-co-N-hydroxymethylacrylamide-co-3-(trimethoxysilyl)propyl methacrylate)-b-poly(e-caprolactone) (P(NIPAAm-co-HMAAm-co-MPMA)-b-PCL) bearing thermosensitivity as well as biodegradability was synthesized for the production of hollow spheres. A three-step approach was employed to prepare shell cross-linked (SCL), thermoresponsive hybrid hollow spheres: (1) micellization of P(NIPAAm-co-HMAAm-co-MPMA)-b-PCL, (2) cross-linking of the hydrophilic shell via acid-catalyzed sol−gel process, and then (3) degrading the PCL core with an enzyme. Transmission electron microscopy (TEM) studies and size measurements showed that the resultant hollow spheres exhibited regularly globular shape with diameter of around 170 nm. The structures of the SCL micelles and the hollow spheres were characterized by Fourier-transform infrared (FT-IR) measurements and laser light scattering (LLS) analyses. The SCL hollow spheres showed reversible dispersion/aggregation in respon...

Formation of Reversible Shell Cross-Linked Micelles from the Biodegradable Amphiphilic Diblock Copolymer Poly(l-cysteine)-block-Poly(l-lactide)

A novel biodegradable diblock copolymer, poly(L-cysteine)-b-poly(L-lactide) (PLC-b-PLLA), was synthesized by ring-opening polymerization (ROP) of N-carboxyanhydride of beta-benzyloxycarbonyl-L-cysteine (ZLC-NCA) with amino-terminated poly(L-lactide) (NH 2-PLLA) as a macroinitiator in a convenient way. The diblock copolymer and its precursor were characterized by (1)H NMR, Fourier transform infrared (FT-IR), gel permeation chromatography (GPC), and X-ray photoelectron spectroscopy (XPS) measurements. The length of each block polymer could be tailored by molecular design and the ratios of feeding monomers. The cell adhesion and cell spread on the PZLC-b-PLLA and PLC-b-PLLA films were enhanced compared to those on pure PLA film. PLC-b-PLLA can self-assemble to form micelles in aqueous media. A pyrene probe is used to demonstrate the micelle formation of PLC-b-PLLA in aqueous solution. Due to the ease of disulfide exchange with thiols, the obtained micelles are reversible shell cross-linked (SCL) micelles. The morphology and size of the micelles are studied by dynamic light scattering (DLS) and environmental scanning electron microscopy (ESEM).

Synthesis and Applications of Shell Cross-Linked Thermoresponsive Hybrid Micelles Based on Poly(N-isopropylacrylamide-co-3-(trimethoxysilyl)propyl methacrylate)-b-poly(methyl methacrylate)

Shell cross-linked (SCL) thermoresponsive hybrid micelles consisting of a cross-linked thermoresponsive hybrid hydrophilic shell and a hydrophobic core domain were synthesized from poly(N-isopropylacrylamide-co-3- (trimethoxysilyl)propyl methacrylate)-b-polymethyl methacrylate (P(NIPAAm-co-MPMA)-b-PMMA) amphiphilic block copolymers. Transmission electron microscopy (TEM) images showed that the SCL micelles formed regularly globular nanoparticles. The SCL micelles showed reversible dispersion/aggregation in response to temperature cycles through an outer polymer shell lower critical solution temperature (LCST) for PNIPAAm at around 33 degrees C, observed by turbidity measurements and dynamic light scattering (DLS). The drug loading and in vitro drug release properties of the SCL micelles bearing a silica-reinforced PNIPAAm shell were further studied, which showed that the SCL micelles exhibited a much improved entrapment efficiency (EE) as well as a slower release rate which allowed the entrapped molecules to be slowly released over a much longer period of time as compared with pure PNIPAAm-b-PMMA micelles.

“Decoration” of Shell Cross-Linked Reverse Polymer Micelles Using ATRP: A New Route to Stimuli-Responsive Nanoparticles

We demonstrate the use of atom transfer radical polymerization (ATRP) to graft polymers onto preformed shell cross-linked reverse micelles (SCRM). Reverse polymer micelles are first obtained in organic solvents and stabilized by cross-linking of the shell using the photoinduced dimerization of coumarin groups (>310 nm). The structurally locked SCRM are then used as micellar macroinitiators for further polymerization from their surface of monomers such as styrene and dimethylaminoethyl methacrylate (DMAEMA) via ATRP. The decoration of an outer corona of PDMAEMA renders the nanoparticles containing a hydrophilic core soluble in water, with the solubility being sensitive to changes in pH and temperature. In addition, such decorated SCRM are light-responsive. The photoinduced cleavage of cyclobutane bridges (<260 nm) leads to the de-cross-linking of the shell and thus the disintegration of the micellar aggregates. The characterization results, using size-exclusion chromatography (SEC), dynamic light scatterin...

Aldehyde Surface-Functionalized Shell Cross-Linked Micelles with pH-Tunable Core Swellability and Their Bioconjugation with Lysozyme

Two approaches were attempted for the syntheses of α-aldehyde terminally functionalized double hydrophilic diblock or triblock copolymers of 2-(dimethylamino)ethyl methacrylate (DMA), 2-(diethylamino)ethyl methacrylate (DEA), and oligo(ethylene glycol)methyl ether methacrylate (OEGMA) via an atom transfer radical polymerization (ATRP) process. The first approach employed 2-(2,2-dimethoxyethoxy)ethyl α-bromoisobutyrate as the ATRP initiator for the sequential polymerization of DMA and DEA monomers. However, after deprotection of the terminal acetal into aldehyde groups, the obtained Ald-PDMA-b-PDEA diblock copolymer was prone to aldol condensation at alkaline pH, leading to extensive formation of dimers. Directly using 4-aldehydephenyl α-bromoisobutyrate as the ATRP initiator, the sequential polymerization of OEGMA, DMA, and DEA led to the successful preparation of the α-aldehyde terminally functionalized triblock copolymer, Ald-POEGMA-b-PDMA-b-PDEA. This triblock copolymer molecularly dissolves in acidic media and self-assembles into three-layer onion-like micelles consisting of PDEA cores, PDMA inner shells, and POEGMA outer coronas at alkaline pH. Selective cross-linking of the PDMA inner shell with 2-bis(2-iodoethoxy)ethane led to structurally stabilized shell cross-linked (SCL) micelles functionalized with surface aldehyde groups. Possessing the PDEA cores, the obtained SCL micelles exhibited reversible pH-responsive swelling/deswelling behavior, as revealed by dynamic laser light scattering. The surface aldehyde groups of SCL micelles enabled their facile conjugation with a model protein, lysozyme, via the formation of Schiff bases. The micelle−protein bioconjugate was characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The previous results suggest promising applications of SCL micelles in fields such as targeted drug delivery and controlled release.