Dually responsive poly[(N,N-diethylaminoethyl methacrylate)-b-(N-isopropyl acrylamide)]s (P(DEAEMA-b-NIPAM)s) capable of "schizophrenic" aggregation in aqueous solution were synthesized via aqueous reversible addition-fragmentation chain transfer (RAFT) polymerization. The nanoassembly morphologies, dictated by the hydrophilic mass fraction, can be controlled by the polymer block lengths, solution pH, and temperature. Both P(DEAEMA 98 -b-NIPAM 209 ) (52.5 wt % NIPAM) and P(DEAEMA 98b-NIPAM 392 ) (70.8 wt % NIPAM) self-assemble into PDEAEMA-core PNIPAM-shell spherical micelles with a hydrodynamic radii (R h ) of 21 and 25 nm, respectively, at temperatures below the lower critical solution temperature of PNIPAM and at solution pH values greater than the pK a of PDEAEMA. The two block copolymers, however, display quite different temperature-responsive behaviors at pH < 7.5. At elevated temperatures (>42 °C) P(DEAEMA 98 -b-NIPAM 209 ) forms spherical micelles (R h =28 nm) with hydrophobic PNIPAM cores stabilized by a hydrophilic PDEAEMA shell. By contrast, P(DEAEMA 98 -b-NIPAM 392 ) assembles into vesicles (R h =99 nm) above 38 °C. The nanostructures were characterized by a combination of dynamic and static light scattering as well as transmission electron microscopy and are being investigated for their potential application as drug delivery vehicles. † Paper number 143 in a series on Water-Soluble Polymers.
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 R-methoxypoly(ethylene oxide)-b-poly[N-(3aminopropyl)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 macrochain 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 Nhydroxysuccinimidyl 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 pK a 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.
A temperature-responsive triblock copolymer, R-methoxypoly(ethylene oxide)-b-poly(N-(3-aminopropyl)methacrylamide)-b-poly(N-isopropylacrylamide) (mPEO-PAPMA-PNIP-AM), was synthesized via aqueous RAFT (aRAFT) polymerization. At room temperature, the polymer is hydrophilic and exists as unimers in aqueous solution. Increasing the solution temperature above the lower critical solution temperature (LCST) of the PNIPAM block leads to self-assembly into micelles with PNI-PAM cores, PAPMA shells, and mPEO coronas with hydrodynamic diameter (D h ) values of ca. 52 nm. The PAPMA shell was crosslinked with terephthaldicarboxaldehyde (TDA) at pH 9.0 to generate shell cross-linked (SCL) micelles with cleavable imine linkages. The reversible pH-and temperature-dependent formation and cleavage of the (SCL) micelles was followed by dynamic light scattering and NMR spectroscopy. As well, the release of the model hydrophobic drug prednisolone 21-acetate (PA) from loaded SCL micelles was studied at specific pH and temperature conditions. PA was released at pH < 6.0 as hydrolytic cleavage of the imine cross-links within the swollen SCL micelles occurred. Such "pH-triggered" release behavior conceptually demonstrates that the reversible SCL micelles prepared by this simple procedure from temperature-responsive triblock copolymers have promise as therapeutic nanocarriers in biomedicine.
Reversible addition-fragmentation chain transfer (RAFT) polymerization was utilized to prepare multiresponsive, self-assembling amphiphilic poly[(N,N-dimethylaminoethyl methacrylate)
x
-b-(N-isopropylacrylamide)
y
] (DMAEMA
x
-b-NIPAM
y
). Controlling block lengths, solution pH, and NaCl concentration to elicit changes in the hydrophilic mass fraction resulted in specific morphological changes upon thermally induced assembly. At y = 102 (68 wt % DMAEMA), DMAEMA165-b-NIPAM102 copolymers self-assemble into simple core−shell micelles (58 nm). Increasing y to 202 (48 wt % DMAEMA) leads to a mixture of spherical micelles (78 nm) and worm-like micelles (D = 50−100 nm, L = 400−500 nm). Further increasing y to 435 (36 wt % DMAEMA) produces vesicular structures (179 nm). Significantly, reversible assembly of these nanostructures from the present stimuli-responsive diblock copolymers can be accomplished directly in aqueous media without the necessity of dialysis or manipulation with cosolvents. Additionally, the associated nanostructures can be shell cross-linked above the critical aggregation temperature via the in situ formation of gold nanoparticles yielding assemblies with long-term aqueous stability.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.